[ { "cxVersion": "2.0.0", "hasFragments": false }, { "metaData": [ { "name": "attributeDeclarations", "elementCount": 1 }, { "name": "networkAttributes", "elementCount": 1 }, { "name": "nodes", "elementCount": 248 }, { "name": "edges", "elementCount": 395 }, { "name": "status", "elementCount": 1 } ] }, { "networkAttributes": [ { "name": "SAMHD1 A565T Innate Immune Multi-Scale Causal Network (Bio-FOM Reference)", "description": "248-node, 426-edge multi-scale biophysical causal graph linking atomistic SAMHD1 mechanics to mitochondrial VDAC1/POLG disruption, cGAS/STING and NLRP3 parallel loops, and systemic ME/CFS phenotype.", "version": "2.0", "organism": "Homo sapiens", "provenance": "glass-cannon/Med-docs" } ] }, { "nodes": [ { "id": 1, "v": { "name": "cGAS", "id_str": "cgas", "full_name": "Cyclic GMP-AMP synthase (MB21D1)", "compartment": "cytosol", "class": "sensor", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting" ], "summary": "Length-dependent cytosolic dsDNA sensor. Binds DNA as a 2:2 ladder and switches on its nucleotidyl-transferase activity.", "detail": "cGAS does not care where the DNA came from \u2014 only that it is double-stranded and in the cytosol. In SAMHD1-deficient cells the cytosolic DNA is overwhelmingly mitochondrial, and the entire ISG signature is cGAS-dependent: double knockout of SAMHD1 + cGAS abolishes ISGs, and IMSB301 normalises the ISG signature in AGS PBMCs.", "samhd1_effect": "A565T haploinsufficiency supplies cGAS with three ligand streams at once: mtDNA fragments through the VDAC1 macropore, ssDNA fragments from collapsed replication forks, and LINE-1 cDNA that escaped restriction. This is the entry point of Loop A.", "db_xrefs": "{\"uniprot\": \"Q8N884\", \"ensembl\": \"ENSG00000164430\", \"hgnc\": \"HGNC:21367\", \"chembl\": \"CHEMBL3706170\"}", "kinetics": "{\"DNA_length_threshold_bp\": 45, \"cGAMP_synth_kcat_s\": 1.2, \"Kd_dsDNA_nM\": 25}" }, "x": 260.0, "y": 60.0, "z": 480.0 }, { "id": 2, "v": { "name": "2\u20323\u2032-cGAMP", "id_str": "cgamp", "full_name": "Cyclic GMP-AMP, the cGAS second messenger", "compartment": "cytosol", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting" ], "summary": "Non-canonical 2\u2032-5\u2032/3\u2032-5\u2032 cyclic dinucleotide; the highest-affinity endogenous STING agonist known.", "detail": "cGAMP also passes to neighbouring cells through gap junctions and via SLC19A1 import, which is how one stressed cell can raise the interferon tone of a whole tissue field.", "samhd1_effect": "" }, "x": 160.0, "y": 160.0, "z": 420.0 }, { "id": 3, "v": { "name": "STING", "id_str": "sting", "full_name": "Stimulator of interferon genes (TMEM173 / STING1)", "compartment": "er", "class": "adaptor", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "ankib1" ], "summary": "ER-resident dimer. cGAMP binding closes its ligand-binding lid, triggering polymerisation and ER exit.", "detail": "Activated STING traffics ER \u2192 ERGIC \u2192 Golgi. Only after it reaches the ERGIC does its C-terminal tail recruit TBK1 in a way that permits IRF3 phosphorylation \u2014 trafficking is part of the switch, not incidental to it.", "samhd1_effect": "STING is one of the five ANKIB1 K11-Ub substrates held constitutively primed by SAMHD1 loss. Primed STING lowers the threshold for TBK1/IRF3 scaffold assembly, producing tonic rather than pulsatile interferon.", "db_xrefs": "{\"uniprot\": \"Q86WV6\", \"ensembl\": \"ENSG00000184584\", \"hgnc\": \"HGNC:27962\", \"chembl\": \"CHEMBL3714578\"}", "kinetics": "{\"Kd_cGAMP_nM\": 4.8, \"oligomerization_threshold_nM\": 15}" }, "x": 40.0, "y": 300.0, "z": 360.0 }, { "id": 4, "v": { "name": "STING\u00b0(Golgi)", "id_str": "sting-golgi", "full_name": "Palmitoylated STING at the ERGIC/Golgi \u2014 the signalling-competent pool", "compartment": "er", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting" ], "summary": "Palmitoylation at Cys88/91 clusters STING into signalling-competent microdomains on Golgi membranes.", "detail": "This step is where the covalent-inhibitor class (H-151, nitrofurans) acts, and it is the reason STING signalling is terminated by lysosomal degradation rather than by dephosphorylation.", "samhd1_effect": "" }, "x": 180.0, "y": 360.0, "z": 260.0 }, { "id": 5, "v": { "name": "RIG-I", "id_str": "rigi", "full_name": "Retinoic acid-inducible gene I (DDX58)", "compartment": "cytosol", "class": "sensor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs" ], "summary": "Senses short 5\u2032-triphosphate blunt-ended dsRNA \u2014 the signature of viral replication intermediates.", "detail": "ATP-driven translocation along duplex RNA releases the CARD domains from autorepression; the freed CARDs nucleate MAVS filaments in a prion-like manner.", "samhd1_effect": "" }, "x": -60.0, "y": -220.0, "z": 540.0 }, { "id": 6, "v": { "name": "MDA5", "id_str": "mda5", "full_name": "Melanoma differentiation-associated protein 5 (IFIH1)", "compartment": "cytosol", "class": "sensor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs", "retro" ], "summary": "Senses long duplex RNA by cooperative filament assembly. The retroelement sensor of the RLR family.", "detail": "MDA5 has no end-recognition mechanism \u2014 it polymerises along the length of a duplex, so it reads duplex LENGTH as the danger signal. Its physiological self-antigen problem is Alu inverted-repeat dsRNA in 3\u2032UTRs, which ADAR1 p150 must continuously edit to keep below the MDA5 threshold. IFIH1 gain-of-function is AGS7; ADAR1 loss is AGS6. Both converge on this node.", "samhd1_effect": "SAMHD1 deficiency activates MDA5 in a cGAS/STING-INDEPENDENT manner \u2014 a genuinely separate arm from Loop A. SAMHD1 normally sequesters immunostimulatory dsRNA in LLPS condensates; losing that sequestration exposes duplex RNA that MDA5 reads as viral." }, "x": 80.0, "y": -180.0, "z": 560.0 }, { "id": 7, "v": { "name": "LGP2", "id_str": "lgp2", "full_name": "Laboratory of genetics and physiology 2 (DHX58)", "compartment": "cytosol", "class": "sensor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs" ], "summary": "CARD-less RLR that tunes MDA5 filament nucleation \u2014 accelerates it at low levels, caps it at high levels.", "detail": "", "samhd1_effect": "" }, "x": 160.0, "y": -260.0, "z": 520.0 }, { "id": 8, "v": { "name": "cytosolic dsRNA", "id_str": "dsrna-cyt", "full_name": "Immunostimulatory cytosolic double-stranded RNA", "compartment": "cytosol", "class": "ligand", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs", "retro" ], "summary": "Mixed pool: Alu inverted repeats, mitochondrial bidirectional transcripts, HERV transcripts, viral replication intermediates.", "detail": "", "samhd1_effect": "SAMHD1 normally holds this pool inside LLPS condensates. Haploinsufficiency releases it into free solution where MDA5 can polymerise on it." }, "x": 0.0, "y": -120.0, "z": 620.0 }, { "id": 9, "v": { "name": "mito dsRNA", "id_str": "mtdsrna", "full_name": "Mitochondrial bidirectional-transcription double-stranded RNA", "compartment": "mitochondrion", "class": "ligand", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs", "mito" ], "summary": "Both mtDNA strands are transcribed fully; the resulting complementary RNAs form duplexes that PNPASE and SUV3 normally degrade.", "detail": "When mitochondrial RNA-degradosome capacity is exceeded, mito-dsRNA escapes to the cytosol and is read by MDA5 \u2014 stressor S5 in the Convergent Mitochondrial Catastrophe figure.", "samhd1_effect": "" }, "x": 440.0, "y": 80.0, "z": 340.0 }, { "id": 10, "v": { "name": "MAVS", "id_str": "mavs", "full_name": "Mitochondrial antiviral-signalling protein (IPS-1 / VISA / Cardif)", "compartment": "mitochondrion", "class": "adaptor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs", "mito" ], "summary": "Tail-anchored in the outer mitochondrial membrane. RLR CARDs seed self-propagating MAVS prion-like filaments.", "detail": "MAVS is why RNA sensing is a mitochondrial event. Filament assembly is all-or-nothing and requires an intact membrane potential \u2014 which links \u0394\u03a8m collapse directly to signalling competence.", "samhd1_effect": "SAMHD1 impairs type I IFN induction through the MAVS\u2013IKK\u03b5\u2013IRF3/7 axis; losing it de-represses this platform at the same time as the mitochondrion beneath it is being damaged." }, "x": 340.0, "y": 120.0, "z": 250.0 }, { "id": 11, "v": { "name": "MAVS (peroxisomal)", "id_str": "mavs-perox", "full_name": "Peroxisomal MAVS pool", "compartment": "peroxisome", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs" ], "summary": "Drives rapid, IFN-independent ISG expression; the mitochondrial pool supplies the slower type-I IFN amplitude.", "detail": "Two platforms, two kinetics: peroxisomal MAVS gives an immediate local antiviral state, mitochondrial MAVS gives the systemic interferon wave. Only the mitochondrial pool is degraded by mitochondrial injury.", "samhd1_effect": "" }, "x": 580.0, "y": 360.0, "z": -340.0 }, { "id": 12, "v": { "name": "TRAF3", "id_str": "traf3", "full_name": "TNF receptor-associated factor 3", "compartment": "cytosol", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs", "tlr" ], "summary": "K63-Ub ligase that couples MAVS and TRIF to the TBK1/IKK\u03b5 arm (IRF branch).", "detail": "", "samhd1_effect": "" }, "x": 300.0, "y": 200.0, "z": 400.0 }, { "id": 13, "v": { "name": "TRAF6", "id_str": "traf6", "full_name": "TNF receptor-associated factor 6", "compartment": "cytosol", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "rlr-mavs", "tlr", "nfkb" ], "summary": "K63-Ub ligase that couples MAVS/MyD88 to the IKK complex (NF-\u03baB branch).", "detail": "", "samhd1_effect": "" }, "x": 380.0, "y": -120.0, "z": 440.0 }, { "id": 14, "v": { "name": "TLR3", "id_str": "tlr3", "full_name": "Toll-like receptor 3", "compartment": "endosome", "class": "receptor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr" ], "summary": "Endosomal dsRNA receptor. The only TLR that signals exclusively through TRIF.", "detail": "TLR3 \u2192 TRIF \u2192 TBK1 \u2192 IRF3 is also the arm that INDUCES SAMHD1 transcription. That makes it the \u201cupward\u201d therapeutic direction: poly-ICLC agonism raises SAMHD1 protein in a haploinsufficient cell.", "samhd1_effect": "A two-phase onset \u2014 prodromal immune fragility, then a full phenotype precipitated by acute viral infection \u2014 is read as the TLR3\u2192IRF3\u2192SAMHD1 loop failing to terminate the innate response after viral clearance. Losing the induction arm means the response has no scheduled end." }, "x": -260.0, "y": -320.0, "z": 520.0 }, { "id": 15, "v": { "name": "TLR7/8", "id_str": "tlr7", "full_name": "Toll-like receptors 7 and 8 \u2014 endosomal ssRNA sensors", "compartment": "endosome", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr", "retro" ], "summary": "Sense GU-rich ssRNA including HERV and LINE-1 transcripts delivered by autophagy or phagocytosis.", "detail": "", "samhd1_effect": "" }, "x": -380.0, "y": -420.0, "z": 460.0 }, { "id": 16, "v": { "name": "TLR9", "id_str": "tlr9", "full_name": "Toll-like receptor 9 \u2014 endosomal unmethylated CpG DNA sensor", "compartment": "endosome", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr" ], "summary": "Senses hypomethylated CpG DNA \u2014 including mtDNA, which is bacterially hypomethylated by ancestry.", "detail": "Mitochondrial DNA released from dying cells is a TLR9 agonist as well as a cGAS ligand: the same molecule drives two receptors in two compartments.", "samhd1_effect": "" }, "x": -240.0, "y": -480.0, "z": 440.0 }, { "id": 17, "v": { "name": "LL-37", "id_str": "ll37", "full_name": "Cathelicidin antimicrobial peptide LL-37 (CAMP / hCAP18 C-terminal peptide)", "compartment": "extracellular", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr" ], "summary": "A cationic antimicrobial peptide whose second job is to chaperone self-DNA \u2014 converting an inert host molecule into a TLR9 agonist.", "detail": "LL-37 is massively overexpressed in psoriatic skin. It binds extracellular self-DNA electrostatically and condenses it into ordered aggregates that resist nuclease digestion and are retained in the pDC early endosome long enough to signal. Neither component does this alone: LL-37 without DNA is not an interferon stimulus, and self-DNA without LL-37 is not a TLR9 ligand.", "samhd1_effect": "No SAMHD1 link is claimed, and none should be read in. This arm is in the atlas because the phenotype includes enthesitis-predominant psoriatic arthritis and the canonical psoriasis initiation mechanism was absent \u2014 a gap in the DISEASE model rather than in the SAMHD1 cascade. What joins it to the rest of the board is its product, IFN-\u03b1, which is already modelled; it does not join through SAMHD1." }, "x": -580.0, "y": 860.0, "z": 400.0 }, { "id": 18, "v": { "name": "LL-37 \u00b7 self-DNA", "id_str": "ll37-dna", "full_name": "LL-37\u2013self-DNA condensate \u2014 the converted TLR9 agonist", "compartment": "endosome", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr" ], "summary": "The conversion product. This is the node that carries the claim, because self-DNA alone is not a TLR9 agonist and this complex is.", "detail": "Lande et al. showed the discrimination is one of trafficking and residence rather than of chemistry \u2014 the aggregate is delivered to and retained in the early endosome, which is the compartment where a pDC couples TLR9 to IRF7 rather than to NF-\u03baB. Same receptor, same nucleotide sequence, different outcome, because a peptide changed where and for how long the ligand sat.", "samhd1_effect": "" }, "x": -220.0, "y": -420.0, "z": 540.0 }, { "id": 19, "v": { "name": "TLR4", "id_str": "tlr4", "full_name": "Toll-like receptor 4 (LPS / DAMP receptor)", "compartment": "membrane", "class": "receptor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr", "nfkb" ], "summary": "Surface receptor using both MyD88 (NF-\u03baB) and, after endocytosis, TRIF (IRF3). The canonical NLRP3 priming signal.", "detail": "", "samhd1_effect": "TLR4 engagement triggers interferon-independent G0 arrest with SAMHD1-dependent dNTP depletion \u2014 a normal response that a haploinsufficient cell cannot execute properly." }, "x": 80.0, "y": 640.0, "z": 360.0 }, { "id": 20, "v": { "name": "TRIF", "id_str": "trif", "full_name": "TIR-domain-containing adapter-inducing IFN-\u03b2 (TICAM1)", "compartment": "endosome", "class": "adaptor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr", "ankib1" ], "summary": "The IRF3-directing TLR adaptor; also a bona fide ANKIB1 K11-Ub substrate.", "detail": "", "samhd1_effect": "Reduced SAMHD1-mediated negative feedback leaves TRIF constitutively K11-primed \u2014 one of the five substrates that lowers the TBK1/IRF3 assembly threshold." }, "x": -300.0, "y": -340.0, "z": 590.0 }, { "id": 21, "v": { "name": "MyD88", "id_str": "myd88", "full_name": "Myeloid differentiation primary response 88", "compartment": "endosome", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr", "nfkb" ], "summary": "Assembles the Myddosome with IRAK4/IRAK1 \u2192 TRAF6 \u2192 NF-\u03baB, and in pDCs \u2192 IRF7 directly.", "detail": "", "samhd1_effect": "" }, "x": -400.0, "y": -340.0, "z": 400.0 }, { "id": 22, "v": { "name": "IRAK4/1", "id_str": "irak14", "full_name": "Interleukin-1 receptor-associated kinases 4 and 1", "compartment": "endosome", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr", "nfkb" ], "summary": "Myddosome kinases; IRAK1 phosphorylates IRF7 directly in the plasmacytoid dendritic-cell IFN burst.", "detail": "", "samhd1_effect": "" }, "x": -450.0, "y": -400.0, "z": 370.0 }, { "id": 23, "v": { "name": "ANKIB1", "id_str": "ankib1", "full_name": "Ankyrin repeat and IBR domain-containing 1 \u2014 K11-Ub E3 ligase", "compartment": "cytosol", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ankib1", "cgas-sting", "tlr" ], "summary": "Assembles K11-linked ubiquitin chains on STING, TRIF, NEMO, OPTN \u2014 and on itself. The gain-control knob of the whole system.", "detail": "Betrancourt/Rieser/Walczak (Nat Cell Biol 2026) established K11 ubiquitination as the linkage that drives type-I/III interferon induction downstream of both cGAS\u2013STING and TLR3/4. ANKIB1 is not a terminal effector \u2014 it sets the THRESHOLD at which TBK1/IRF3 scaffolds assemble. That is why the resulting phenotype is a moderate, unrelenting tonic interferon output rather than discrete cytokine surges.", "samhd1_effect": "This is the framework's central gain-control claim. SAMHD1 loss primes all five substrates at once: dNTPase failure primes STING via cGAS, reduced negative feedback primes TRIF, reduced NF-\u03baB suppression primes NEMO. Worse, ANKIB1 AUTO-ubiquitinates during activation and is degraded by the proteasome \u2014 so the master negative regulator destroys itself exactly when it is needed most. A self-terminating feedback controller cannot hold homeostasis under chronic drive. Predicted readout: ANKIB1 protein REDUCED at baseline in A565T cells, restored by amlexanox (Arms 5\u20136) but NOT by upadacitinib (Arm 2).", "db_xrefs": "{\"uniprot\": \"Q9P2G1\", \"ensembl\": \"ENSG00000113889\", \"hgnc\": \"HGNC:19363\"}" }, "x": 60.0, "y": 220.0, "z": 80.0 }, { "id": 24, "v": { "name": "K11-Ub chains", "id_str": "k11ub", "full_name": "Lysine-11-linked polyubiquitin \u2014 the interferon-permissive linkage", "compartment": "cytosol", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ankib1" ], "summary": "Distinct from K48 (degradation) and K63 (canonical signalling). K11 loading on the five substrates lowers scaffold-assembly threshold.", "detail": "Measurable with linkage-specific antibodies (clone 2A3/2E6) or K11-TUBE reagents \u2014 which is what makes K11-Ub/STING loading a candidate patient-stratification biomarker rather than a purely theoretical node.", "samhd1_effect": "" }, "x": 120.0, "y": 280.0, "z": 20.0 }, { "id": 25, "v": { "name": "OPTN", "id_str": "optn", "full_name": "Optineurin \u2014 TBK1 scaffold recruiter and mitophagy receptor", "compartment": "cytosol", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ankib1", "mitophagy" ], "summary": "Dual role: recruits TBK1 into signalling scaffolds, and acts as an autophagy receptor on ubiquitinated mitochondria.", "detail": "OPTN sits at the exact junction where this disease turns on itself \u2014 the same protein that amplifies interferon signalling is the one needed to clear the damaged mitochondria producing the ligands.", "samhd1_effect": "" }, "x": 180.0, "y": 340.0, "z": 120.0 }, { "id": 26, "v": { "name": "NEMO", "id_str": "nemo", "full_name": "NF-\u03baB essential modulator (IKK\u03b3)", "compartment": "cytosol", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "ankib1" ], "summary": "Regulatory subunit of the IKK complex; ubiquitin-chain receptor and ANKIB1 K11-Ub substrate.", "detail": "", "samhd1_effect": "Loss of SAMHD1's NF-\u03baB-suppressive function leaves NEMO constitutively primed \u2014 the third of the five ANKIB1 substrates.", "db_xrefs": "{\"uniprot\": \"Q9Y6K9\", \"ensembl\": \"ENSG00000269386\", \"hgnc\": \"HGNC:5961\"}" }, "x": -20.0, "y": -100.0, "z": 260.0 }, { "id": 27, "v": { "name": "TBK1", "id_str": "tbk1", "full_name": "TANK-binding kinase 1", "compartment": "cytosol", "class": "kinase", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "rlr-mavs", "tlr", "ankib1" ], "summary": "The master switch linking every upstream sensor to IRF3/IRF7 transactivation. Trans-autophosphorylates at Ser172.", "detail": "TBK1 activation requires clustering on a scaffold, not simple ligand binding \u2014 which is precisely why K11-Ub priming of the scaffold components is a gain-control mechanism rather than an on/off switch.", "samhd1_effect": "p-TBK1(Ser172) is unaffected by JAK1 inhibition, making it the cleanest pharmacologic separator across the study arms: it moves with amlexanox (Arms 5\u20136) and not with upadacitinib (Arm 2).", "db_xrefs": "{\"uniprot\": \"Q9UHD2\", \"ensembl\": \"ENSG00000183747\", \"hgnc\": \"HGNC:11584\", \"chembl\": \"CHEMBL5686\"}", "kinetics": "{\"p_Ser172_turnover_s\": 3.4, \"amlexanox_IC50_uM\": 5.6}" }, "x": 120.0, "y": 260.0, "z": 220.0 }, { "id": 28, "v": { "name": "IKK\u03b5", "id_str": "ikke", "full_name": "Inhibitor of \u03baB kinase \u03b5 (IKBKE)", "compartment": "cytosol", "class": "kinase", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "rlr-mavs", "ankib1", "metabolic" ], "summary": "TBK1 paralogue; the dominant IRF7 kinase and an independent driver of metabolic inflammation.", "detail": "Reilly et al. showed TBK1/IKK\u03b5 inhibition improves obesity-related metabolic dysfunction \u2014 which is why amlexanox lands on both the interferon and the metabolic arms of this phenotype at once.", "samhd1_effect": "SAMHD1 occupies IRF7's inhibitory domain and physically prevents IKK\u03b5-mediated phosphorylation. Haploinsufficiency removes that block, so IKK\u03b5 phosphorylates IRF7 constitutively.", "db_xrefs": "{\"uniprot\": \"Q14164\", \"ensembl\": \"ENSG00000143464\", \"hgnc\": \"HGNC:5962\", \"chembl\": \"CHEMBL5687\"}" }, "x": 240.0, "y": 280.0, "z": 160.0 }, { "id": 29, "v": { "name": "IRF3", "id_str": "irf3", "full_name": "Interferon regulatory factor 3", "compartment": "cytosol", "class": "tf", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "rlr-mavs", "tlr" ], "summary": "Constitutively expressed first-wave IFN transcription factor. Phosphorylation \u2192 dimerisation \u2192 nuclear import.", "detail": "IRF3 drives IFN-\u03b2 (IFNB1) and a subset of ISGs directly, without needing new protein synthesis \u2014 it is the immediate response. It also drives SAMHD1 transcription, closing a normally protective loop.", "samhd1_effect": "The IRF3\u2192SAMHD1 induction arm is the therapeutic \"upward\" direction (Arms 3\u20134). It is also the reason amlexanox carries a genome-stability tradeoff: suppressing IRF3 lowers SAMHD1 transcription in a cell that is already haploinsufficient.", "db_xrefs": "{\"uniprot\": \"Q14653\", \"ensembl\": \"ENSG00000126456\", \"hgnc\": \"HGNC:6118\"}" }, "x": -20.0, "y": 160.0, "z": 60.0 }, { "id": 30, "v": { "name": "IRF7", "id_str": "irf7", "full_name": "Interferon regulatory factor 7 \u2014 the amplification-loop factor", "compartment": "cytosol", "class": "tf", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "tlr", "metabolic" ], "summary": "The second-wave amplifier: itself an ISG, so once interferon starts, IRF7 rises and drives more interferon.", "detail": "IRF7 is the master regulator of the IFN-\u03b1 subtypes. Because IRF7 is interferon-inducible, IRF3 \u2192 IFN-\u03b2 \u2192 IFNAR \u2192 IRF7 \u2192 IFN-\u03b1 is a positive-feedback amplifier with no intrinsic ceiling except its brakes.", "samhd1_effect": "SAMHD1 physically occupies IRF7's inhibitory domain. This is Brake 1 of the four failed brakes: haploinsufficiency removes IRF7 restraint, giving constitutive second-wave interferon. IRF7 also transactivates MCP-1 SPECIFICALLY in visceral adipocytes \u2014 the mechanistic link from an immune gene to android-pattern adiposity and diet-refractory steatosis.", "db_xrefs": "{\"uniprot\": \"Q92985\", \"ensembl\": \"ENSG00000185507\", \"hgnc\": \"HGNC:6122\"}" }, "x": -100.0, "y": 40.0, "z": 160.0 }, { "id": 31, "v": { "name": "IKK\u03b2", "id_str": "ikk", "full_name": "Inhibitor of \u03baB kinase beta (IKBKB) \u2014 the canonical catalytic subunit", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Phosphorylates I\u03baB\u03b1 on Ser32/36, marking it for K48-Ub and proteasomal destruction. The canonical arm runs through here; IKK\u03b1 carries the non-canonical one.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"O15111\", \"ensembl\": \"ENSG00000104365\", \"hgnc\": \"HGNC:5960\"}" }, "x": -80.0, "y": -140.0, "z": 220.0 }, { "id": 32, "v": { "name": "I\u03baB\u03b1", "id_str": "ikba", "full_name": "Nuclear factor of \u03baB inhibitor alpha (NFKBIA)", "compartment": "cytosol", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Masks the NF-\u03baB nuclear localisation signal. Its degradation is the licensing step for NF-\u03baB nuclear entry.", "detail": "I\u03baB\u03b1 is itself an NF-\u03baB target gene, giving the pathway its classic oscillatory negative feedback \u2014 oscillation that a constitutively driven system flattens into a plateau.", "samhd1_effect": "" }, "x": -160.0, "y": -100.0, "z": 180.0 }, { "id": 33, "v": { "name": "NF-\u03baB p65/p50", "id_str": "nfkb", "full_name": "Nuclear factor \u03baB \u2014 RelA/p50 heterodimer", "compartment": "cytosol", "class": "tf", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "inflammasome" ], "summary": "Drives the NLRP3 priming signal (NLRP3 + pro-IL-1\u03b2 transcription), IL-6, IL-23, TNF-\u03b1 and I\u03baB\u03b1.", "detail": "NF-\u03baB is signal 1 of the two-signal inflammasome model. Without it, NLRP3 and pro-IL-1\u03b2 are not present in sufficient quantity for signal 2 to matter.", "samhd1_effect": "SAMHD1 suppresses innate immune responses by inhibiting the NF-\u03baB pathway directly. Its loss is Brake 4 of the four failed brakes \u2014 de-suppressed IKK gives IL-1\u03b2/IL-23 \u2192 Th17 \u2192 the psoriatic arthritis axis.", "db_xrefs": "{\"uniprot\": \"P19838\", \"ensembl\": \"ENSG00000109320\", \"hgnc\": \"HGNC:7794\"}" }, "x": -200.0, "y": -180.0, "z": 120.0 }, { "id": 34, "v": { "name": "VDAC1", "id_str": "vdac1", "full_name": "Voltage-dependent anion channel 1 \u2014 outer-membrane porin", "compartment": "mitochondrion", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "cgas-sting" ], "summary": "The most abundant outer-membrane protein and the gatekeeper of metabolite flux \u2014 and, when it oligomerises, of DNA escape.", "detail": "Monomeric VDAC1 passes ATP/ADP, NAD\u207a and Ca\u00b2\u207a. Oligomeric VDAC1 forms a large-conductance macropore wide enough to pass mtDNA fragments into the cytosol. The switch between the two states is the single most therapeutically addressable event in this figure.", "samhd1_effect": "SAMHD1 physically interacts with VDAC1 on the outer membrane, and Diaz-Griffero's group showed SAMHD1 must be present INSIDE the mitochondrial compartment to prevent \u0394\u03a8m collapse and mtDNA release. Losing that interaction opens the macropore. VBIT-4 in SAMHD1-KO monocytes prevents cytosolic mtDNA release and FULLY abolishes the spontaneous ISG response \u2014 which is the strongest single piece of evidence that Loop A is VDAC1-gated rather than oxidation-dependent.", "db_xrefs": "{\"uniprot\": \"P21796\", \"ensembl\": \"ENSG00000213886\", \"hgnc\": \"HGNC:12682\"}" }, "x": 580.0, "y": 140.0, "z": 260.0 }, { "id": 35, "v": { "name": "VDAC1 macropore", "id_str": "vdac1-oligo", "full_name": "Oligomerised VDAC1 \u2014 the large-conductance DNA-permissive pore", "compartment": "mitochondrion", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "cgas-sting" ], "summary": "The primary constitutive mtDNA-fragment escape route in SAMHD1 haploinsufficiency.", "detail": "Driven by mtROS and amplified by SLC25A33 (PNC1) upregulation. Distinct from mPTP: this route operates without \u0394\u03a8m collapse, which is why it can run constitutively in a cell that is still alive and dividing.", "samhd1_effect": "" }, "x": 700.0, "y": 100.0, "z": 300.0 }, { "id": 36, "v": { "name": "mPTP", "id_str": "mptp", "full_name": "Mitochondrial permeability transition pore (ANT/CypD/ATP-synthase dimer)", "compartment": "mitochondrion", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito" ], "summary": "Second mtDNA escape route, opening downstream of \u0394\u03a8m collapse and Ca\u00b2\u207a/ROS overload.", "detail": "TNF-\u03b1 drives sublethal chronic mPTP opening via ROS, producing a persistent cytochrome-c leak rather than a lethal burst \u2014 stressor S8, and the reason apoptotic priming here is chronic rather than executioner.", "samhd1_effect": "" }, "x": 640.0, "y": -160.0, "z": 180.0 }, { "id": 37, "v": { "name": "BIK", "id_str": "bik", "full_name": "BCL2-interacting killer \u2014 BH3-only apoptotic primer", "compartment": "mitochondrion", "class": "effector", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "mitophagy" ], "summary": "Directly upregulated by SAMHD1; sequesters BECN1, biasing the cell toward apoptosis over mitophagy.", "detail": "BIK knockdown blunts apoptosis and cytochrome-c release in THP-1 cells. Germline BIK + SAMHD1 variants co-segregate as prostate cancer susceptibility genes \u2014 a rare instance where the mitochondrial arm and the oncologic arm of this framework touch the same two genes.", "samhd1_effect": "" }, "x": 380.0, "y": -220.0, "z": 140.0 }, { "id": 38, "v": { "name": "BAX / BAK", "id_str": "baxbak", "full_name": "Pro-apoptotic effectors \u2014 MOMP pore formers", "compartment": "mitochondrion", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito" ], "summary": "Macropore formation for cytochrome-c release; sublethal (\"minority\") MOMP also permits mtDNA herniation.", "detail": "", "samhd1_effect": "" }, "x": 460.0, "y": -240.0, "z": 200.0 }, { "id": 39, "v": { "name": "cytochrome c", "id_str": "cytc", "full_name": "Cytochrome c \u2014 ETC electron shuttle and apoptotic signal", "compartment": "mitochondrion", "class": "metabolite", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito" ], "summary": "Its release is simultaneously a bioenergetic loss (Complex III\u2192IV gap) and an apoptotic signal.", "detail": "", "samhd1_effect": "" }, "x": 520.0, "y": -240.0, "z": 240.0 }, { "id": 40, "v": { "name": "DRP1", "id_str": "drp1", "full_name": "Dynamin-related protein 1 \u2014 fission GTPase", "compartment": "mitochondrion", "class": "enzyme", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "mitophagy" ], "summary": "STING activation drives DRP1-mediated fission far in excess of fusion, fragmenting the network.", "detail": "Fragmentation raises surface-to-volume ratio, raises mtROS, and multiplies the number of VDAC1 oligomerisation sites \u2014 the geometry itself becomes part of the feedback loop.", "samhd1_effect": "" }, "x": 300.0, "y": -160.0, "z": 360.0 }, { "id": 41, "v": { "name": "MFN1/2", "id_str": "mfn", "full_name": "Mitofusins 1 and 2 \u2014 outer-membrane fusion GTPases", "compartment": "mitochondrion", "class": "enzyme", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "mitophagy", "isg" ], "summary": "ISGylated by ISG15, which blocks the PINK1/Parkin mitophagy programme downstream of them.", "detail": "The IRF1 \u2192 PARP12 \u2192 ISG15 \u2192 MFN1/2 ISGylation axis is the replacement anchor for the retracted Sliter 2018 paper. ISG15 knockdown restores mitophagic flux, \u0394\u03a8m and ATP.", "samhd1_effect": "" }, "x": 740.0, "y": -140.0, "z": 200.0 }, { "id": 42, "v": { "name": "PINK1", "id_str": "pink1", "full_name": "PTEN-induced kinase 1 \u2014 depolarisation sensor", "compartment": "mitochondrion", "class": "kinase", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy", "mito" ], "summary": "Accumulates on the outer membrane only when import fails \u2014 i.e. only on depolarised mitochondria.", "detail": "In a healthy mitochondrion PINK1 is imported and cleaved by PARL. \u0394\u03a8m collapse stops import, so PINK1 stabilises on the surface and phosphorylates ubiquitin at Ser65, recruiting Parkin. This is the sensor that is supposed to flag exactly the mitochondria this disease creates.", "samhd1_effect": "" }, "x": 660.0, "y": -200.0, "z": 320.0 }, { "id": 43, "v": { "name": "Parkin", "id_str": "parkin", "full_name": "Parkin RBR E3 ubiquitin ligase (PRKN)", "compartment": "mitochondrion", "class": "enzyme", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy" ], "summary": "Amplifies the pS65-Ub signal into a dense ubiquitin coat that autophagy receptors read.", "detail": "", "samhd1_effect": "The pathway is intact but jammed downstream: ISGylated MFN1/2 and ISGylated BECN1 both block flux, so damaged mitochondria are flagged and then never cleared." }, "x": 760.0, "y": -200.0, "z": 360.0 }, { "id": 44, "v": { "name": "TOM/TIM", "id_str": "tom20", "full_name": "Translocases of the outer and inner membranes", "compartment": "mitochondrion", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito" ], "summary": "Protein import machinery. \u0394\u03a8m-dependent: when the potential collapses, import stops and PINK1 accumulates.", "detail": "", "samhd1_effect": "" }, "x": 280.0, "y": 60.0, "z": 340.0 }, { "id": 45, "v": { "name": "PNC1 (SLC25A33)", "id_str": "pnc1", "full_name": "Pyrimidine nucleotide carrier 1 \u2014 inner-membrane dNTP importer", "compartment": "mitochondrion", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Imports cytosolic (deoxy)nucleotides across the inner membrane into the matrix \u2014 including guanine, not only pyrimidines.", "detail": "PNC1 sits at the intersection of BOTH loops: it feeds the matrix dNTP pool that stalls POLG (\u2192 ox-mtDNA \u2192 NLRP3, Loop B), and its upregulation independently drives mtDNA synthesis and VDAC1 oligomerisation via mtROS (\u2192 cGAS, Loop A). That makes it the only node in the study upstream of both NLRP3 and VDAC1.\n\nThe name is misleading and the distinction matters here. Di Noia 2014 reconstituted both carriers in proteoliposomes: SLC25A33 antiports uracil, thymine and cytosine (deoxy)nucleoside di- and triphosphates \u2014 and BOTH carriers also transport guanine (deoxy)nucleotides, though neither transports adenine. That is what licenses this atlas to route a dGTP-SKEWED cytosolic pool through carriers named for pyrimidines. Without it the purple stream would have a chemical gap at exactly its load-bearing step.", "samhd1_effect": "Cytosolic dNTP excess from dNTPase failure floods PNC1/PNC2. Arm 10 tests this with PLP (vitamin B6), which inhibits SLC25A33 transport and is clinically trivial to obtain. The bifurcating prediction is the sharpest experiment in the study: suppress Loop B only \u2192 the loops are independently gated; suppress both \u2192 PNC1-driven mtROS is the dominant driver of VDAC1 oligomerisation." }, "x": 420.0, "y": 80.0, "z": 180.0 }, { "id": 46, "v": { "name": "PNC2 (SLC25A36)", "id_str": "pnc2", "full_name": "Pyrimidine nucleotide carrier 2", "compartment": "mitochondrion", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Second inner-membrane carrier; uniports and antiports cytosine/uracil nucleotides plus guanine, and shares the overload with PNC1.", "detail": "", "samhd1_effect": "" }, "x": 480.0, "y": 100.0, "z": 150.0 }, { "id": 47, "v": { "name": "Complex I", "id_str": "etc-i", "full_name": "NADH:ubiquinone oxidoreductase", "compartment": "mitochondrion", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Suppressed by sustained STAT1/2 signalling; also the dominant site of reverse-electron-transport ROS.", "detail": "", "samhd1_effect": "" }, "x": 340.0, "y": -80.0, "z": 160.0 }, { "id": 48, "v": { "name": "Complex III", "id_str": "etc-iii", "full_name": "Cytochrome bc1 complex", "compartment": "mitochondrion", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Directly inhibited by ceramide, and suppressed by ISG-driven transcriptional programmes.", "detail": "The IL-1\u03b2/NF-\u03baB axis drives ceramide synthesis, and ceramide inhibits Complex III directly while permeabilising the inner membrane and raising mPTP propensity. One cytokine, three simultaneous injuries.", "samhd1_effect": "" }, "x": 450.0, "y": -100.0, "z": 140.0 }, { "id": 49, "v": { "name": "Complex IV", "id_str": "etc-iv", "full_name": "Cytochrome c oxidase", "compartment": "mitochondrion", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Terminal oxidase; its activity falls with cytochrome-c leak and with mtDNA-encoded subunit loss.", "detail": "", "samhd1_effect": "" }, "x": 560.0, "y": -100.0, "z": 140.0 }, { "id": 50, "v": { "name": "ATP synthase", "id_str": "etc-v", "full_name": "Complex V \u2014 F1F0 ATP synthase", "compartment": "mitochondrion", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Uses the proton-motive force to make ATP; runs in reverse to defend \u0394\u03a8m when the ETC fails, burning ATP.", "detail": "", "samhd1_effect": "" }, "x": 660.0, "y": -80.0, "z": 160.0 }, { "id": 51, "v": { "name": "\u0394\u03a8m", "id_str": "deltapsi", "full_name": "Mitochondrial inner-membrane potential", "compartment": "mitochondrion", "class": "metabolite", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "The master state variable of the organelle: sets ATP output, protein import, PINK1 stability and mPTP threshold.", "detail": "", "samhd1_effect": "Samhd1-KO causes measurable \u0394\u03a8m collapse and M1 macrophage skewing. Collapse here is not a downstream symptom \u2014 it re-enters the loop by stopping PINK1 import and opening mPTP." }, "x": 520.0, "y": -180.0, "z": 300.0 }, { "id": 52, "v": { "name": "cardiolipin", "id_str": "cardiolipin", "full_name": "Cardiolipin \u2014 inner-membrane signature phospholipid", "compartment": "mitochondrion", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "mitophagy" ], "summary": "Externalised cardiolipin is itself a mitophagy \"eat-me\" signal and an NLRP3-binding surface.", "detail": "", "samhd1_effect": "" }, "x": 400.0, "y": -160.0, "z": 260.0 }, { "id": 53, "v": { "name": "ceramide", "id_str": "ceramide", "full_name": "Ceramide \u2014 sphingolipid second messenger", "compartment": "er", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "inflammasome" ], "summary": "Synthesised downstream of IL-1\u03b2/NF-\u03baB; inhibits Complex III and permeabilises the inner membrane.", "detail": "", "samhd1_effect": "" }, "x": -40.0, "y": 340.0, "z": 420.0 }, { "id": 54, "v": { "name": "mtDNA nucleoid", "id_str": "mtdna", "full_name": "Mitochondrial DNA packaged with TFAM into nucleoids", "compartment": "mitochondrion", "class": "ligand", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "cgas-sting" ], "summary": "~16.6 kb circular genome at 100\u20131000 copies per cell. Hypomethylated, unprotected by histones, adjacent to the ROS source.", "detail": "mtDNA is the perfect autoantigen: bacterial in ancestry, CpG-hypomethylated, chemically damaged by its own neighbourhood, and present in high copy number. Everything the innate immune system evolved to treat as foreign.", "samhd1_effect": "" }, "x": 520.0, "y": 0.0, "z": 240.0 }, { "id": 55, "v": { "name": "POLG", "id_str": "polg", "full_name": "DNA polymerase gamma \u2014 the only mtDNA replicase", "compartment": "mitochondrion", "class": "enzyme", "evidence": "I", "evidence_tier": "L1_in_silico", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Fidelity and processivity both degrade when the matrix dNTP pool is skewed, especially by excess dGTP.", "detail": "POLG stalling produces mtDNA strand breaks, and the uncontrolled neosynthesis that follows yields the OXIDISED product \u2014 ox-mtDNA \u2014 which is the NLRP3 ligand. This is the purple stream.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P54098\", \"ensembl\": \"ENSG00000140521\", \"hgnc\": \"HGNC:9179\"}" }, "x": 450.0, "y": 20.0, "z": 270.0 }, { "id": 56, "v": { "name": "TFAM", "id_str": "tfam", "full_name": "Mitochondrial transcription factor A \u2014 nucleoid packaging protein", "compartment": "mitochondrion", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Compacts and protects mtDNA. TFAM insufficiency alone is enough to release mtDNA and prime cGAS.", "detail": "West et al. 2015 showed that mtDNA stress from TFAM depletion primes the antiviral interferon response \u2014 the foundational demonstration that the mitochondrion can start an interferon reaction with no pathogen present.", "samhd1_effect": "" }, "x": 590.0, "y": 20.0, "z": 220.0 }, { "id": 57, "v": { "name": "TWNK / mtSSB", "id_str": "twnk", "full_name": "Twinkle helicase and mitochondrial single-strand binding protein", "compartment": "mitochondrion", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito" ], "summary": "The rest of the mtDNA replisome; stalls with POLG when nucleotide supply is unbalanced.", "detail": "", "samhd1_effect": "" }, "x": 630.0, "y": 50.0, "z": 270.0 }, { "id": 58, "v": { "name": "matrix dNTP pool", "id_str": "mito-dntp", "full_name": "Mitochondrial deoxynucleotide pool", "compartment": "mitochondrion", "class": "metabolite", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Independently maintained from the cytosolic pool \u2014 but only as long as PNC1/PNC2 import is balanced.", "detail": "Upgraded S on Liu 2026: cytosolic dNTP accumulating behind a disabled SAMHD1 is transported into mitochondria through nucleotide carriers, supplying excess building blocks for mtDNA neosynthesis and bypassing the CMPK2 salvage pathway that normally rate-limits it. Demonstrated in cells from zebrafish, mice and humans, with a myeloid-conditional Samhd1 knockout, and reversed by blocking the transport step.", "samhd1_effect": "The perturbation here is qualitative as well as quantitative: it is the dGTP skew, not just total concentration, that impairs POLG fidelity." }, "x": 440.0, "y": 20.0, "z": 210.0 }, { "id": 59, "v": { "name": "mtROS", "id_str": "mtros", "full_name": "Mitochondrial reactive oxygen species", "compartment": "mitochondrion", "class": "metabolite", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "inflammasome" ], "summary": "The hub metabolite: oxidises mtDNA, drives VDAC1 oligomerisation, primes NLRP3, and damages the ETC that made it.", "detail": "", "samhd1_effect": "" }, "x": 500.0, "y": -60.0, "z": 310.0 }, { "id": 60, "v": { "name": "ox-mtDNA", "id_str": "oxmtdna", "full_name": "Oxidised mitochondrial DNA \u2014 the NLRP3 ligand", "compartment": "cytosol", "class": "ligand", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "inflammasome" ], "summary": "Product of dNTP overload \u2192 POLG stalling \u2192 uncontrolled mtDNA neosynthesis, oxidised in situ. Activates NLRP3, NOT cGAS.", "detail": "This species distinction is the correction at the heart of the project's mitochondrial manuscript. ox-mtDNA is the direct NLRP3 ligand demonstrated in SAMHD1-null and obese macrophages (Loop B). It is NOT the species that drives the ISG signature \u2014 that is the unoxidised/mixed fragment pool escaping through VDAC1 (Loop A). Same organelle, different oxidation state, different sensor, different loop, different rescue point.", "samhd1_effect": "" }, "x": 460.0, "y": -180.0, "z": 320.0 }, { "id": 61, "v": { "name": "cytosolic mtDNA fragments", "id_str": "mtdna-frag", "full_name": "Unoxidised / mixed mtDNA fragments in the cytosol \u2014 the cGAS ligand", "compartment": "cytosol", "class": "ligand", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "cgas-sting" ], "summary": "Escapes via the VDAC1 macropore (primary, constitutive) and mPTP (secondary). Bound by cGAS \u2192 Loop A.", "detail": "The proof is pharmacological and clean: VBIT-4 prevents release and abolishes the spontaneous ISG response; IMSB301 (cGAS inhibitor) normalises the ISG signature in AGS PBMCs. Both confirm the route is cGAS-dependent and VDAC1-gated rather than oxidation-dependent.", "samhd1_effect": "" }, "x": 400.0, "y": 60.0, "z": 400.0 }, { "id": 62, "v": { "name": "succinate", "id_str": "succinate", "full_name": "Succinate \u2014 TCA-cycle inflammatory signal", "compartment": "mitochondrion", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Accumulates in M1 macrophages, inhibits prolyl hydroxylases, stabilises HIF-1\u03b1 under normoxia.", "detail": "", "samhd1_effect": "" }, "x": 480.0, "y": -120.0, "z": 320.0 }, { "id": 63, "v": { "name": "HIF-1\u03b1", "id_str": "hif1a", "full_name": "Hypoxia-inducible factor 1-alpha", "compartment": "cytosol", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "metabolic", "inflammasome" ], "summary": "Stabilised normoxically by succinate \u2192 aerobic glycolysis (Warburg shift) and IL-1\u03b2 transcription.", "detail": "", "samhd1_effect": "" }, "x": 300.0, "y": -60.0, "z": 520.0 }, { "id": 64, "v": { "name": "ATP output", "id_str": "atp", "full_name": "Cellular ATP production capacity", "compartment": "mitochondrion", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "The bottom line of the whole mitochondrial arm \u2014 and the readout that JAK inhibition did NOT rescue.", "detail": "", "samhd1_effect": "This node is the JAK-refractory residual. When JAK1 inhibition clears the inflammatory arm and the fatigue and metabolic dysfunction stay, what is left is bioenergetic \u2014 Loop B and the direct mitochondrial injuries, both of which run independently of JAK\u2013STAT." }, "x": 720.0, "y": -40.0, "z": 220.0 }, { "id": 65, "v": { "name": "aerobic glycolysis", "id_str": "glycolysis", "full_name": "Compensatory fermentative / aerobic glycolysis (Warburg shift)", "compartment": "cytosol", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "metabolic", "mito" ], "summary": "Emergency metabolic switch when OXPHOS fails; prevents bioenergetic necrosis but fuels lactate and pyruvate overflow.", "detail": "Marcucci & Rumio (2026) demonstrated that compensatory fermentative glycolysis acts as an emergency survival switch when mitochondrial membrane potential collapses, preventing catastrophic necrotic lysis. However, the resulting pyruvate overflow pyruvilates STAT1 (Zuo 2026) and lactate accumulation drives H3K18 lactylation (Ziogas 2025).", "samhd1_effect": "" }, "x": 200.0, "y": -80.0, "z": 480.0 }, { "id": 66, "v": { "name": "lactate", "id_str": "lactate", "full_name": "Cytosolic and extracellular lactic acid accumulation", "compartment": "cytosol", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "metabolic", "clinical" ], "summary": "Glycolytic end-product; fuels nuclear histone lactylation and delivers a synovial entrapment signal for Th17 cells.", "detail": "", "samhd1_effect": "" }, "x": 120.0, "y": -180.0, "z": 460.0 }, { "id": 67, "v": { "name": "H3K18la", "id_str": "h3k18la", "full_name": "Histone H3 Lys18 lactylation (H3K18la) chromatin lock", "compartment": "nucleus", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "metabolic", "genome", "clinical" ], "summary": "Persistent epigenetic chromatin lock responsible for multi-day post-exertional malaise (PEM) and immune exhaustion.", "detail": "Ziogas et al. (Cell 2025) and Marcucci & Rumio (2026) established that chronic lactate accumulation drives enzymatic histone lactylation (H3K18la) at enhancer loci. This modification persists long after exertion terminates, locking macrophages and immune cells in a refractory exhaustion state that directly models prolonged PEM crashes.", "samhd1_effect": "" }, "x": -280.0, "y": -60.0, "z": -100.0 }, { "id": 68, "v": { "name": "BECN1", "id_str": "becn1", "full_name": "Beclin-1 \u2014 autophagy initiation scaffold", "compartment": "cytosol", "class": "adaptor", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy", "isg" ], "summary": "ISGylated by ISG15, which competes with the activating K63-Ub mark and independently blocks autophagic flux.", "detail": "This is the second, ISG15-dependent brake \u2014 distinct from the MFN1/2 block and additive to it. The project manuscript calls the ISG15\u2013BECN1 block the KEYSTONE stressor (S6): it is what converts transient mitochondrial damage into permanent accumulation.", "samhd1_effect": "" }, "x": 60.0, "y": -360.0, "z": -280.0 }, { "id": 69, "v": { "name": "LC3-II", "id_str": "lc3", "full_name": "Microtubule-associated protein 1 light chain 3, lipidated form", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy" ], "summary": "Autophagosome membrane marker; LC3-II/I ratio with p62 is the standard flux readout in Arm 1.", "detail": "", "samhd1_effect": "" }, "x": 0.0, "y": -300.0, "z": -220.0 }, { "id": 70, "v": { "name": "p62 / SQSTM1", "id_str": "p62", "full_name": "Sequestosome-1 \u2014 ubiquitin-binding autophagy receptor", "compartment": "cytosol", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy" ], "summary": "Accumulates when flux is blocked \u2014 the readout that separates \"more autophagosomes\" from \"working autophagy\".", "detail": "", "samhd1_effect": "" }, "x": -60.0, "y": -380.0, "z": -300.0 }, { "id": 71, "v": { "name": "mTORC1", "id_str": "mtor", "full_name": "Mechanistic target of rapamycin complex 1", "compartment": "lysosome", "class": "kinase", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy", "metabolic" ], "summary": "Constitutively active under chronic inflammation; retains MITF/TFEB in the cytoplasm.", "detail": "", "samhd1_effect": "" }, "x": 260.0, "y": -380.0, "z": -320.0 }, { "id": 72, "v": { "name": "MITF / TFEB", "id_str": "mitf", "full_name": "Lysosomal biogenesis transcription factors", "compartment": "lysosome", "class": "tf", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy" ], "summary": "Cytoplasmically retained by mTORC1 \u2192 lysosomal hydrolase genes under-transcribed.", "detail": "", "samhd1_effect": "" }, "x": 310.0, "y": -460.0, "z": -440.0 }, { "id": 73, "v": { "name": "Cathepsin D", "id_str": "ctsd", "full_name": "CTSD \u2014 principal lysosomal aspartyl protease", "compartment": "lysosome", "class": "enzyme", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy" ], "summary": "Under-produced when MITF is retained; autolysosomes fail to degrade their cargo.", "detail": "", "samhd1_effect": "The SAMHD1 \u2192 mTOR \u2192 MITF \u2192 CTSD axis was described in macrophage autophagy-lysosomal failure. Damaged mitochondria stay trapped upstream of a non-functional lysosome, amplifying mtROS." }, "x": 160.0, "y": -460.0, "z": -400.0 }, { "id": 74, "v": { "name": "DNase II", "id_str": "dnase2", "full_name": "Deoxyribonuclease II alpha (DNASE2) \u2014 the lysosomal acid DNase", "compartment": "lysosome", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy", "cgas-sting", "retro" ], "summary": "The terminal step of DNA disposal: whatever autophagy and phagocytosis deliver, DNase II is what actually destroys it.", "detail": "DNase II is acid-dependent and lysosome-restricted, so it only works in a compartment that has been properly acidified and properly stocked. Human DNASE2 deficiency is a type-I interferonopathy, and in mice Dnase2 loss is embryonically lethal from interferon \u2014 rescued by deleting the interferon receptor, and by deleting cGAS or STING. Undigested DNA in a failing lysosome is sufficient, by itself, to drive the exact signature this whole framework is about.", "samhd1_effect": "This is a missing EDGE between two arms the atlas already had, not a new subgraph. The mTOR\u2192MITF\u2192CTSD axis is already modelled as under-producing lysosomal hydrolases \u2014 and DNase II is one of them. So the same lysosomal failure that traps damaged mitochondria upstream also stops the cell degrading the mtDNA it did manage to engulf. Mitophagy failure and cGAS ligand supply turn out to be the same lesion seen from two directions." }, "x": 100.0, "y": -520.0, "z": -460.0 }, { "id": 75, "v": { "name": "DNASE1L3", "id_str": "dnase1l3", "full_name": "Deoxyribonuclease 1-like 3 \u2014 the secreted chromatin nuclease", "compartment": "extracellular", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "cgas-sting" ], "summary": "The only nuclease that digests chromatin inside apoptotic microparticles. Loss-of-function causes familial SLE.", "detail": "It handles the extracellular half of the same problem: DNA that leaves a dying cell packaged in membrane, where soluble DNase I cannot reach it. Relevant here because the framework already posits continuous sub-lethal and lytic death \u2014 pyroptosis, and now necroptosis \u2014 as ongoing sources of extracellular DNA.", "samhd1_effect": "" }, "x": -60.0, "y": 860.0, "z": -220.0 }, { "id": 76, "v": { "name": "autolysosome", "id_str": "autolysosome", "full_name": "Autophagosome\u2013lysosome fusion product", "compartment": "lysosome", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mitophagy" ], "summary": "Where mitophagy should terminate. In this disease the cargo arrives and is not destroyed.", "detail": "", "samhd1_effect": "" }, "x": 80.0, "y": -440.0, "z": -360.0 }, { "id": 77, "v": { "name": "PNC1/PNC2 dNTP Bypass", "id_str": "pnc1-dntp-bypass", "full_name": "Mitochondrial pyrimidine nucleotide carrier 1/2 (SLC25A33 / SLC25A36) import bypass", "compartment": "mitochondrion", "class": "metabolite", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "mito", "metabolic" ], "summary": "Cytosolic dNTP excess floods PNC1/PNC2, bypassing CMPK2 salvage and causing matrix pool asymmetry.", "detail": "Liu 2026 (Science 391:eadq9006) demonstrated that cytosolic dNTP accumulating behind disabled SAMHD1 is transported into mitochondria via SLC25A33/36, supplying excess substrate for aberrant mtDNA neosynthesis.", "samhd1_effect": "Direct consequence of SAMHD1 dNTPase failure; the metabolic bridge between cytosolic dNTP excess and mitochondrial matrix DNA damage.", "db_xrefs": "{\"uniprot\": \"Q9BSK2\", \"ensembl\": \"ENSG00000117010\", \"hgnc\": \"HGNC:20658\"}", "kinetics": "{\"dGTP_Vmax_nmol_min_mg\": 3.8, \"Km_cytosolic_dGTP_uM\": 12}" }, "x": 140.0, "y": -180.0, "z": -220.0 }, { "id": 78, "v": { "name": "IFN-\u03b2", "id_str": "ifnb", "full_name": "Interferon beta-1 (IFNB1)", "compartment": "extracellular", "class": "cytokine", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "cgas-sting" ], "summary": "The single-gene first-wave interferon. IRF3-driven, requires no new protein synthesis.", "detail": "", "samhd1_effect": "Tonic and moderate-amplitude rather than surging \u2014 the signature the concept note names NACI (Non-Acute Chronic Interferonopathy).", "db_xrefs": "{\"uniprot\": \"P01574\", \"ensembl\": \"ENSG00000171855\", \"hgnc\": \"HGNC:5434\"}" }, "x": -80.0, "y": 920.0, "z": 100.0 }, { "id": 79, "v": { "name": "IFN-\u03b1 (13 subtypes)", "id_str": "ifna", "full_name": "Interferon alpha family", "compartment": "extracellular", "class": "cytokine", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "The second-wave amplifier set, driven by IRF7 rather than IRF3.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P01562\", \"ensembl\": \"ENSG00000188383\", \"hgnc\": \"HGNC:5431\"}" }, "x": 100.0, "y": 940.0, "z": 40.0 }, { "id": 80, "v": { "name": "IFN-\u03b3", "id_str": "ifng", "full_name": "Interferon gamma \u2014 the type II interferon", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "clinical" ], "summary": "Different receptor, different STAT dimer, overlapping ISG output. Drives the collagen-catabolic arm.", "detail": "Tonic IFN-\u03b3 suppresses collagen-I transcription via STAT1 antagonism of TGF-\u03b2/Smad3 while coordinately upregulating MMP-1 and MMP-3 in dermal fibroblasts \u2014 the established mechanism behind the connective-tissue and fascial failure phenotype.", "samhd1_effect": "" }, "x": 360.0, "y": 900.0, "z": -120.0 }, { "id": 81, "v": { "name": "IFN-\u03bb", "id_str": "ifnl", "full_name": "Type III interferon (IL-28/IL-29)", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "ankib1" ], "summary": "Epithelial-restricted receptor, identical downstream JAK module. Also driven by the ANKIB1 K11-Ub node.", "detail": "", "samhd1_effect": "" }, "x": -280.0, "y": 900.0, "z": -60.0 }, { "id": 82, "v": { "name": "IL-6", "id_str": "il6", "full_name": "Interleukin-6", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "clinical" ], "summary": "NF-\u03baB output; dose-dependently elevated in ME/CFS PBMCs after poly I:C stimulation.", "detail": "", "samhd1_effect": "" }, "x": -420.0, "y": 860.0, "z": 180.0 }, { "id": 83, "v": { "name": "TNF-\u03b1", "id_str": "tnfa", "full_name": "Tumour necrosis factor alpha", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "mito" ], "summary": "Drives sublethal chronic mPTP opening via ROS \u2014 a persistent cytochrome-c leak rather than an execution signal.", "detail": "", "samhd1_effect": "" }, "x": -160.0, "y": 880.0, "z": 340.0 }, { "id": 84, "v": { "name": "IL-23", "id_str": "il23", "full_name": "Interleukin-23", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "clinical" ], "summary": "NF-\u03baB output driving Th17 differentiation \u2014 the psoriatic arthritis axis.", "detail": "", "samhd1_effect": "" }, "x": 20.0, "y": 860.0, "z": -300.0 }, { "id": 85, "v": { "name": "IL-17A", "id_str": "il17a", "full_name": "Interleukin-17A \u2014 Th17 effector", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "clinical" ], "summary": "With TNF-\u03b1, drives enthesitis at tendon\u2013bone and fascial insertions.", "detail": "", "samhd1_effect": "" }, "x": 180.0, "y": 840.0, "z": -360.0 }, { "id": 86, "v": { "name": "MCP-1 / CCL2", "id_str": "mcp1", "full_name": "Monocyte chemoattractant protein 1", "compartment": "extracellular", "class": "cytokine", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "metabolic", "clinical" ], "summary": "IRF7 transactivates MCP-1 specifically in VISCERAL adipocytes, not subcutaneous ones.", "detail": "", "samhd1_effect": "This tissue specificity is the mechanistic explanation for android-pattern adiposity with no subcutaneous lower-body accumulation \u2014 a metabolic phenotype produced by an immune transcription factor." }, "x": 480.0, "y": 840.0, "z": 40.0 }, { "id": 87, "v": { "name": "GDF15", "id_str": "gdf15", "full_name": "Growth differentiation factor 15 \u2014 mitochondrial stress cytokine", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "metabolic", "mito" ], "summary": "The canonical circulating readout of integrated mitochondrial stress; elevated post-exercise in ME/CFS.", "detail": "", "samhd1_effect": "" }, "x": -540.0, "y": 840.0, "z": -60.0 }, { "id": 88, "v": { "name": "IFNAR1", "id_str": "ifnar1", "full_name": "Interferon alpha/beta receptor subunit 1", "compartment": "membrane", "class": "receptor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Low-affinity subunit, constitutively associated with TYK2. Ligand affinity here sets ISG-response breadth.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P17181\", \"ensembl\": \"ENSG00000142166\", \"hgnc\": \"HGNC:5432\"}" }, "x": -160.0, "y": 640.0, "z": 160.0 }, { "id": 89, "v": { "name": "IFNAR2", "id_str": "ifnar2", "full_name": "Interferon alpha/beta receptor subunit 2", "compartment": "membrane", "class": "receptor", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "isg" ], "summary": "High-affinity subunit bound to JAK1; the docking site for the USP18 negative-feedback brake.", "detail": "", "samhd1_effect": "USP18 is stabilised by ISG15 and is the primary IFNAR2 brake. In this disease the brake is present and even upregulated \u2014 it is simply overwhelmed by an upstream genetic drive it cannot reach.", "db_xrefs": "{\"uniprot\": \"P48551\", \"ensembl\": \"ENSG00000159110\", \"hgnc\": \"HGNC:5433\"}" }, "x": -20.0, "y": 640.0, "z": 210.0 }, { "id": 90, "v": { "name": "JAK1", "id_str": "jak1", "full_name": "Janus kinase 1", "compartment": "cytosol", "class": "kinase", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Shared by type I, type II and type III interferon receptors. The pharmacologic choke point of the whole ISG arm.", "detail": "", "samhd1_effect": "JAK1-selective inhibition clears the inflammatory arm of this disease almost completely and the bioenergetic arm barely at all. What it fails to move is therefore a map of everything downstream of the genetic lesion that does not route through JAK\u2013STAT: Loop B, the direct mitochondrial injuries, and the upstream ANKIB1 priming that JAK inhibition never reaches.", "db_xrefs": "{\"uniprot\": \"P23458\", \"ensembl\": \"ENSG00000162434\", \"hgnc\": \"HGNC:6190\", \"chembl\": \"CHEMBL2835\"}" }, "x": -180.0, "y": 540.0, "z": 140.0 }, { "id": 91, "v": { "name": "TYK2", "id_str": "tyk2", "full_name": "Tyrosine kinase 2", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Partners JAK1 on IFNAR1. Human TYK2 deficiency is well tolerated, which is what makes it a clean drug target.", "detail": "TYK2 also serves IL-12 and IL-23, so TYK2 blockade hits the Th17/psoriatic arm as well as the interferon arm \u2014 relevant given the confirmed PsA diagnosis.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P29597\", \"ensembl\": \"ENSG00000105397\", \"hgnc\": \"HGNC:12440\", \"chembl\": \"CHEMBL3553\"}" }, "x": -20.0, "y": 540.0, "z": 210.0 }, { "id": 92, "v": { "name": "JAK2", "id_str": "jak2", "full_name": "Janus kinase 2", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Partners JAK1 on IFNGR. Also the erythropoietin/thrombopoietin kinase \u2014 the source of JAK-inhibitor cytopenias.", "detail": "", "samhd1_effect": "" }, "x": 340.0, "y": 500.0, "z": -160.0 }, { "id": 93, "v": { "name": "IFNGR1/2", "id_str": "ifngr", "full_name": "Interferon gamma receptor", "compartment": "membrane", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Uses JAK1 + JAK2 \u2192 STAT1 homodimer (GAF) \u2192 GAS elements.", "detail": "", "samhd1_effect": "" }, "x": 360.0, "y": 600.0, "z": -160.0 }, { "id": 94, "v": { "name": "IFNLR1/IL10RB", "id_str": "ifnlr", "full_name": "Type III interferon receptor", "compartment": "membrane", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Epithelial-restricted; converges on the same JAK1/TYK2 \u2192 ISGF3 module.", "detail": "", "samhd1_effect": "" }, "x": -340.0, "y": 600.0, "z": -60.0 }, { "id": 95, "v": { "name": "IL-1R1", "id_str": "il1r", "full_name": "Interleukin-1 receptor type 1", "compartment": "membrane", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome", "nfkb" ], "summary": "Reads IL-1\u03b2 back into MyD88 \u2192 NF-\u03baB \u2014 how Loop B keeps its own priming signal alive.", "detail": "", "samhd1_effect": "" }, "x": 340.0, "y": 620.0, "z": 220.0 }, { "id": 96, "v": { "name": "TNFR1", "id_str": "tnfr", "full_name": "Tumour necrosis factor receptor 1", "compartment": "membrane", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "mito" ], "summary": "NF-\u03baB activation and, via ROS, chronic sublethal mPTP opening.", "detail": "", "samhd1_effect": "" }, "x": -240.0, "y": 620.0, "z": 360.0 }, { "id": 97, "v": { "name": "STAT1", "id_str": "stat1", "full_name": "Signal transducer and activator of transcription 1", "compartment": "cytosol", "class": "tf", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "metabolic" ], "summary": "Y701-phosphorylated by JAK1/TYK2. Forms ISGF3 with STAT2/IRF9, or GAF homodimers downstream of IFN-\u03b3.", "detail": "", "samhd1_effect": "SAMHD1-KO monocytes show persistent JAK\u2013STAT1/2 and ISG activation that JAK inhibition normalises. STAT1 also directly represses PGC-1\u03b1 transcription, so the interferon arm suppresses mitochondrial biogenesis as a transcriptional side effect.", "db_xrefs": "{\"uniprot\": \"P42224\", \"ensembl\": \"ENSG00000115415\", \"hgnc\": \"HGNC:11362\"}" }, "x": -260.0, "y": 420.0, "z": 200.0 }, { "id": 98, "v": { "name": "STAT2", "id_str": "stat2", "full_name": "Signal transducer and activator of transcription 2", "compartment": "cytosol", "class": "tf", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "Type-I-specific; provides the transactivation domain of ISGF3.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P52630\", \"ensembl\": \"ENSG00000170581\", \"hgnc\": \"HGNC:11363\"}" }, "x": -160.0, "y": 440.0, "z": 240.0 }, { "id": 99, "v": { "name": "IRF9", "id_str": "irf9", "full_name": "Interferon regulatory factor 9 (p48)", "compartment": "cytosol", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "The DNA-binding subunit of ISGF3; supplies ISRE specificity.", "detail": "", "samhd1_effect": "" }, "x": -220.0, "y": 480.0, "z": 300.0 }, { "id": 100, "v": { "name": "ISGF3", "id_str": "isgf3", "full_name": "Interferon-stimulated gene factor 3 (STAT1:STAT2:IRF9)", "compartment": "nucleus", "class": "complex", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "isg" ], "summary": "The type-I interferon transcription complex. Binds ISRE elements across several hundred ISGs.", "detail": "", "samhd1_effect": "" }, "x": -400.0, "y": 300.0, "z": -20.0 }, { "id": 101, "v": { "name": "pyr-STAT1 (K201)", "id_str": "pyr-stat1", "full_name": "STAT1 Lys201 pyruvilation via glycolytic overflow", "compartment": "cytosol", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "metabolic" ], "summary": "Glycolytic overflow covalently pyruvilates STAT1 at Lys201, selectively disrupting STAT1\u2013STAT2 heterodimerization.", "detail": "Zuo et al. (Cell 2026) established that pyruvate modification of STAT1 at Lys201 uncouples Type I IFN antiviral transcriptional output from upstream cGAS\u2013STING drive without blunting NF-\u03baB or STAT3 inflammatory signaling. This resolves the central paradox of heightened viral susceptibility despite sustained interferon pathway activation.", "samhd1_effect": "" }, "x": -200.0, "y": 360.0, "z": 140.0 }, { "id": 102, "v": { "name": "IFNB1 locus", "id_str": "ifnb1-gene", "full_name": "IFN-\u03b2 gene \u2014 the enhanceosome", "compartment": "nucleus", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "rlr-mavs", "tlr" ], "summary": "Requires IRF3 dimers (PRDIII-I) AND NF-\u03baB (PRDII) AND ATF2/c-Jun on the same enhanceosome.", "detail": "The AND-gate architecture is why interferon induction is normally so hard to trigger \u2014 and why priming several inputs at once, as the ANKIB1 node does, changes the output so dramatically.", "samhd1_effect": "" }, "x": -300.0, "y": 220.0, "z": -80.0 }, { "id": 103, "v": { "name": "ISRE elements", "id_str": "isre", "full_name": "Interferon-stimulated response elements", "compartment": "nucleus", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak", "isg" ], "summary": "ISGF3 binding sites upstream of several hundred interferon-stimulated genes.", "detail": "", "samhd1_effect": "" }, "x": -480.0, "y": 180.0, "z": -40.0 }, { "id": 104, "v": { "name": "GAS elements", "id_str": "gas", "full_name": "Gamma-activated sequences", "compartment": "nucleus", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-jak" ], "summary": "STAT1-homodimer (GAF) binding sites \u2014 the type II interferon transcriptional programme.", "detail": "", "samhd1_effect": "" }, "x": -420.0, "y": 280.0, "z": -220.0 }, { "id": 105, "v": { "name": "ISG programme", "id_str": "isg-set", "full_name": "Interferon-stimulated gene set (IFIT1, MX1, OAS, IFI27, ISG15, USP18, RSAD2\u2026)", "compartment": "nucleus", "class": "complex", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "isg", "ifn-jak" ], "summary": "Several hundred genes. The quantitative ISG score is the practical clinical biomarker of this disease.", "detail": "", "samhd1_effect": "The concept note predicts a SERONEGATIVE profile: standard serum cytokine panels normal, but intracellular ISG expression elevated. Workup should target IFN-\u03b1/\u03b2, free ISG15, CXCL10 and ISG scoring rather than a conventional cytokine panel." }, "x": -540.0, "y": 80.0, "z": -120.0 }, { "id": 106, "v": { "name": "PGC-1\u03b1", "id_str": "pgc1a", "full_name": "PPARG coactivator 1-alpha \u2014 master mitochondrial biogenesis regulator", "compartment": "nucleus", "class": "tf", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "metabolic", "mito" ], "summary": "Directly repressed by IFN-I/STAT1 \u2192 mitochondrial biogenesis failure.", "detail": "STAT1-knockout hepatocytes show higher mtDNA content and more mitochondria \u2014 the clean demonstration that this repression is real and reversible. Stressor #5 of the mitochondrial figure.", "samhd1_effect": "" }, "x": -160.0, "y": 120.0, "z": -340.0 }, { "id": 107, "v": { "name": "ISG15", "id_str": "isg15", "full_name": "Interferon-stimulated gene 15 \u2014 ubiquitin-like modifier", "compartment": "cytosol", "class": "effector", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "isg", "mitophagy" ], "summary": "The hinge of the whole ISG arm: stabilises the USP18 brake, but also ISGylates MFN1/2 and BECN1 to block mitophagy.", "detail": "ISG15 is simultaneously protective and destructive here. Free ISG15 stabilises USP18 (the IFNAR2 brake), while conjugated ISG15 shuts down the two autophagy routes the cell needs to clear the mitochondria that are generating the ligand. Knockdown restores flux, \u0394\u03a8m and ATP.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P05161\", \"ensembl\": \"ENSG00000187608\", \"hgnc\": \"HGNC:6153\"}" }, "x": -420.0, "y": 220.0, "z": 300.0 }, { "id": 108, "v": { "name": "USP18", "id_str": "usp18", "full_name": "Ubiquitin-specific peptidase 18 \u2014 the primary IFNAR2 brake", "compartment": "cytosol", "class": "effector", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "isg", "ifn-jak" ], "summary": "Sterically displaces JAK1 from IFNAR2. Its protease activity is dispensable for this function.", "detail": "", "samhd1_effect": "Tonic IFN upregulates ISG15, which stabilises USP18 \u2014 but this compensatory axis is constitutively overwhelmed by the upstream genetic defect. A brake that is fully engaged and still losing.", "db_xrefs": "{\"uniprot\": \"Q9UMW8\", \"ensembl\": \"ENSG00000184981\", \"hgnc\": \"HGNC:12629\"}" }, "x": -320.0, "y": 460.0, "z": 120.0 }, { "id": 109, "v": { "name": "SOCS1/3", "id_str": "socs", "full_name": "Suppressor of cytokine signalling 1 and 3", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "isg", "ifn-jak" ], "summary": "Second brake layer: direct JAK inhibition plus ElonginBC-Cul2 ubiquitination of receptor complexes.", "detail": "", "samhd1_effect": "" }, "x": -380.0, "y": 500.0, "z": 220.0 }, { "id": 110, "v": { "name": "IRF1", "id_str": "irf1", "full_name": "Interferon regulatory factor 1", "compartment": "nucleus", "class": "tf", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "isg" ], "summary": "Drives PARP12 \u2192 ISG15 in the axis that ISGylates MFN1/2 and blocks PINK1/Parkin mitophagy.", "detail": "", "samhd1_effect": "" }, "x": -360.0, "y": 360.0, "z": -180.0 }, { "id": 111, "v": { "name": "NLRP3", "id_str": "nlrp3", "full_name": "NACHT, LRR and PYD domains-containing protein 3", "compartment": "cytosol", "class": "sensor", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Two-signal sensor: NF-\u03baB primes its expression (signal 1), then ox-mtDNA, MSU crystals or K\u207a efflux trigger assembly (signal 2).", "detail": "NLRP3 does not bind its activators the way cGAS binds DNA \u2014 it integrates a set of cell-stress proxies (K\u207a efflux, lysosomal rupture, mtROS, ox-mtDNA, crystals) into one ATPase-driven conformational switch. That integration is why one genetic lesion can drive it from several directions at once.", "samhd1_effect": "SAMHD1 is a metabolic gatekeeper of NLRP3: dNTPase loss ALONE \u2014 with no obesity and no exogenous trigger \u2014 drives cytoplasmic dNTP accumulation, mitochondrial dNTP overload, ox-mtDNA generation and NLRP3 hyperactivation. SAMHD1-deficient animals develop elevated circulating IL-1\u03b2, insulin resistance and steatohepatitis without any diet challenge.", "db_xrefs": "{\"uniprot\": \"Q96P20\", \"ensembl\": \"ENSG00000162711\", \"hgnc\": \"HGNC:16400\", \"chembl\": \"CHEMBL3714856\"}", "kinetics": "{\"ASC_nucleation_rate_s\": 0.85, \"ox_mtDNA_Kd_nM\": 18}" }, "x": 300.0, "y": -300.0, "z": 260.0 }, { "id": 112, "v": { "name": "AIM2", "id_str": "aim2", "full_name": "Absent in melanoma 2 \u2014 cytosolic double-stranded DNA inflammasome sensor", "compartment": "cytosol", "class": "sensor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome", "cgas-sting" ], "summary": "The third cytosolic DNA sensor. Binds dsDNA \u2265 ~80 bp along the backbone and nucleates ASC directly \u2014 no NLRP3, no NEK7, no priming step.", "detail": "AIM2 matters to this atlas because of what it does NOT need. It reads DNA by length rather than sequence, exactly as cGAS does, but its output is an ASC speck rather than an interferon. So the same cytosolic mtDNA fragment pool that feeds Loop A can produce inflammasome activation without ever passing through NLRP3 or ox-mtDNA. In psoriatic lesions AIM2 is activated by cytosolic DNA in keratinocytes, which puts it directly on the confirmed skin/enthesis arm.", "samhd1_effect": "IMPORTANT FOR THE STUDY DESIGN, and untested. The atlas claims ox-mtDNA\u2192NLRP3 and fragments\u2192cGAS run in parallel; AIM2 is the third DNA sensor a reviewer will ask about, and it changes how Arm 9 reads. MCC950 inhibits NLRP3 specifically \u2014 it does NOT touch AIM2. So residual IL-1\u03b2 and residual ASC specks under MCC950 have TWO possible explanations: a caspase-1-independent maturation route (the current reading), or an AIM2 inflammasome the drug was never going to block. Those are distinguishable \u2014 AIM2 specks are NLRP3-independent and NEK7-independent \u2014 and the arm should be designed to tell them apart rather than attributing the residual to the first hypothesis." }, "x": 340.0, "y": -420.0, "z": 380.0 }, { "id": 113, "v": { "name": "IFI16", "id_str": "ifi16", "full_name": "Interferon-gamma-inducible protein 16 \u2014 nuclear and cytosolic DNA sensor", "compartment": "nucleus", "class": "sensor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "cgas-sting", "inflammasome" ], "summary": "The other ALR: predominantly nuclear, and required for full cGAS\u2013STING signalling in human macrophages rather than acting instead of it.", "detail": "IFI16 is a cooperator, not a competitor \u2014 it promotes cGAMP production and STING activation, so knocking it down blunts DNA sensing that would otherwise be called purely cGAS-dependent. Its nuclear localisation also puts it where the genome-stability arm generates its ligands, which is the one place cGAS is normally kept away from chromatin by nucleosome autoinhibition.", "samhd1_effect": "" }, "x": -240.0, "y": 0.0, "z": -40.0 }, { "id": 114, "v": { "name": "NEK7", "id_str": "nek7", "full_name": "NIMA-related kinase 7 \u2014 the NLRP3 licensing partner", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Bridges adjacent NLRP3 subunits; required for oligomerisation and mutually exclusive with mitosis.", "detail": "", "samhd1_effect": "" }, "x": 240.0, "y": -380.0, "z": 340.0 }, { "id": 115, "v": { "name": "ASC speck", "id_str": "asc", "full_name": "Apoptosis-associated speck-like protein containing a CARD (PYCARD)", "compartment": "cytosol", "class": "complex", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Single micron-scale prion-like polymer per cell \u2014 the visible, countable commitment step of the loop.", "detail": "ASC speck formation by immunofluorescence is a primary Arm 1 readout precisely because it is binary and countable. Specks are also released intact and keep processing IL-1\u03b2 extracellularly.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"Q9ULZ3\", \"ensembl\": \"ENSG00000103490\", \"hgnc\": \"HGNC:9360\"}" }, "x": 370.0, "y": -340.0, "z": 180.0 }, { "id": 116, "v": { "name": "caspase-1", "id_str": "casp1", "full_name": "Caspase-1 (p20/p10 active heterotetramer)", "compartment": "cytosol", "class": "enzyme", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Proximity-induced autoprocessing on the ASC filament; cleaves pro-IL-1\u03b2, pro-IL-18 and GSDMD.", "detail": "Note the compartment: caspase-1 activation is strictly cytosolic. It does not happen inside the mitochondrion, even though its trigger comes from there.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P29466\", \"ensembl\": \"ENSG00000137752\", \"hgnc\": \"HGNC:1499\", \"chembl\": \"CHEMBL234\"}" }, "x": 430.0, "y": -320.0, "z": 100.0 }, { "id": 117, "v": { "name": "pro-IL-1\u03b2", "id_str": "proil1b", "full_name": "Inactive interleukin-1\u03b2 precursor", "compartment": "cytosol", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome", "nfkb" ], "summary": "Transcribed by NF-\u03baB (signal 1). Held inert until caspase-1 cleaves it.", "detail": "", "samhd1_effect": "" }, "x": 300.0, "y": -220.0, "z": 60.0 }, { "id": 118, "v": { "name": "IL-1\u03b2", "id_str": "il1b", "full_name": "Interleukin-1 beta \u2014 mature, secreted", "compartment": "extracellular", "class": "cytokine", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "The output of Loop B and the primary readout separating it from the interferon arm.", "detail": "", "samhd1_effect": "Predicted to stay ELEVATED in Arm 2 (upadacitinib) and Arm 5 (amlexanox) despite improving cytokine panels \u2014 because the dNTP\u2192PNC1/2\u2192ox-mtDNA\u2192NLRP3 cascade is upstream of both drug targets. Persistent IL-1\u03b2 in those arms is the formal proof that Loop B is an independent, currently unaddressed therapeutic axis.", "db_xrefs": "{\"uniprot\": \"P01584\", \"ensembl\": \"ENSG00000125538\", \"hgnc\": \"HGNC:5992\", \"chembl\": \"CHEMBL5546\"}" }, "x": 260.0, "y": 880.0, "z": 260.0 }, { "id": 119, "v": { "name": "IL-18", "id_str": "il18", "full_name": "Interleukin-18", "compartment": "extracellular", "class": "cytokine", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Co-matured with IL-1\u03b2; drives IFN-\u03b3 from NK and T cells, linking Loop B back into the interferon arm.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"Q14116\", \"ensembl\": \"ENSG00000150782\", \"hgnc\": \"HGNC:5986\", \"chembl\": \"CHEMBL5749\"}" }, "x": 380.0, "y": 860.0, "z": 200.0 }, { "id": 120, "v": { "name": "GSDMD", "id_str": "gsdmd", "full_name": "Gasdermin D", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Cleaved N-terminal fragment oligomerises into plasma-membrane pores \u2014 the IL-1\u03b2 export route and the pyroptotic lesion.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P57764\", \"ensembl\": \"ENSG00000104518\", \"hgnc\": \"HGNC:13308\"}" }, "x": 440.0, "y": -300.0, "z": 220.0 }, { "id": 121, "v": { "name": "GSDMD pore", "id_str": "gsdmd-pore", "full_name": "Gasdermin-D membrane pore", "compartment": "membrane", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Unconventional secretion channel below lytic threshold; the pyroptotic lesion above it.", "detail": "", "samhd1_effect": "" }, "x": 440.0, "y": 580.0, "z": 300.0 }, { "id": 122, "v": { "name": "pyroptosis", "id_str": "pyroptosis", "full_name": "Inflammatory lytic cell death", "compartment": "cytosol", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "inflammasome" ], "summary": "Spills cytosolic contents \u2014 including mtDNA \u2014 into the extracellular space, re-arming bystander cGAS.", "detail": "This is the dotted cross-link between the two loops: Loop B ends by handing Loop A fresh ligand in the neighbouring cell.", "samhd1_effect": "" }, "x": 540.0, "y": -360.0, "z": 220.0 }, { "id": 123, "v": { "name": "P2X7", "id_str": "p2x7", "full_name": "P2X purinoceptor 7 \u2014 extracellular ATP-gated K\u207a efflux channel", "compartment": "membrane", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "The classic signal-2 route: extracellular ATP from dying cells \u2192 K\u207a efflux \u2192 NLRP3 assembly.", "detail": "", "samhd1_effect": "" }, "x": 500.0, "y": 540.0, "z": 60.0 }, { "id": 124, "v": { "name": "uric acid", "id_str": "urate", "full_name": "Uric acid \u2014 terminal purine catabolite", "compartment": "cytosol", "class": "metabolite", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome", "metabolic" ], "summary": "Excess dGTP is catabolised through the purine pathway; humans lack uricase, so urate is the endpoint.", "detail": "", "samhd1_effect": "" }, "x": 120.0, "y": -280.0, "z": 500.0 }, { "id": 125, "v": { "name": "MSU crystals", "id_str": "msu", "full_name": "Monosodium urate crystals", "compartment": "cytosol", "class": "ligand", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome" ], "summary": "Third NLRP3 input, independent of cGAS status; hits an NLRP3 already sensitised by NF-\u03baB priming.", "detail": "The feedforward trap: one genetic lesion generates both NLRP3 ligands at once. dGTP excess yields ox-mtDNA through POLG stalling AND MSU crystals through purine catabolism \u2014 driving NLRP3 from two directions with a single mutation. Note the honest caveat: MSU crystal presence in SAMHD1-null cells has not been confirmed by peer-reviewed primary data and is carried as inferred input only.", "samhd1_effect": "" }, "x": 180.0, "y": -340.0, "z": 440.0 }, { "id": 126, "v": { "name": "TAK1 / TAB1-3", "id_str": "tak1", "full_name": "TGF-\u03b2-activated kinase 1 (MAP3K7) with its TAB adaptors", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Reads K63-ubiquitin chains through TAB2/3 and phosphorylates IKK\u03b2 at Ser177/181.", "detail": "TAK1 is the branch point where innate signalling splits between NF-\u03baB and the MAPK arm (p38, JNK \u2192 AP-1). Everything upstream \u2014 TRAF6, RIP1, MyD88 \u2014 converges here before the pathway commits.", "samhd1_effect": "" }, "x": -140.0, "y": -220.0, "z": 300.0 }, { "id": 127, "v": { "name": "LUBAC", "id_str": "lubac", "full_name": "Linear ubiquitin chain assembly complex \u2014 HOIP / HOIL-1 / SHARPIN", "compartment": "cytosol", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "ankib1" ], "summary": "The only E3 that builds M1-linear ubiquitin. Conjugates it onto NEMO, stabilising the active IKK complex.", "detail": "LUBAC is what converts a transient receptor event into a sustained IKK signal: linear chains on NEMO create a self-reinforcing recruitment surface. It is also the system in which the ANKIB1 K11 work was done \u2014 the linear-ubiquitin and K11-ubiquitin arms of this atlas come out of the same laboratory, which is why the gain-control framing transfers cleanly between them.", "samhd1_effect": "" }, "x": 40.0, "y": -220.0, "z": 200.0 }, { "id": 128, "v": { "name": "M1-linear Ub", "id_str": "m1ub", "full_name": "Met1-linked (linear) polyubiquitin", "compartment": "cytosol", "class": "metabolite", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Head-to-tail ubiquitin chains \u2014 the linkage NEMO binds with highest affinity.", "detail": "", "samhd1_effect": "" }, "x": -20.0, "y": -180.0, "z": 140.0 }, { "id": 129, "v": { "name": "A20 / TNFAIP3", "id_str": "a20", "full_name": "Tumour necrosis factor alpha-induced protein 3", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "NF-\u03baB target gene and NF-\u03baB terminator: a dual DUB/E3 that strips K63 chains and adds K48.", "detail": "A20 is the pathway's own off-switch, transcribed by the very signal it exists to end. That negative feedback is why healthy NF-\u03baB signalling oscillates rather than plateaus \u2014 and why a constitutive upstream drive produces a fundamentally different waveform, not merely a bigger one.", "samhd1_effect": "" }, "x": -280.0, "y": -260.0, "z": 180.0 }, { "id": 130, "v": { "name": "CYLD", "id_str": "cyld", "full_name": "Cylindromatosis lysine 63 deubiquitinase", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Removes K63 and M1 chains from NEMO, TRAF2/6 and RIP1. A tumour suppressor, for the obvious reason.", "detail": "", "samhd1_effect": "" }, "x": -340.0, "y": -200.0, "z": 240.0 }, { "id": 131, "v": { "name": "OTULIN", "id_str": "otulin", "full_name": "OTU deubiquitinase with linear linkage specificity", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Exclusively hydrolyses M1-linear chains, counter-balancing LUBAC. Its loss causes ORAS, an autoinflammatory syndrome.", "detail": "OTULIN deficiency is instructive here: losing a single linear-chain-editing enzyme is enough to produce systemic autoinflammation in humans. Ubiquitin-linkage editing is not a detail of this pathway \u2014 it is the control system.", "samhd1_effect": "" }, "x": -240.0, "y": -140.0, "z": 300.0 }, { "id": 132, "v": { "name": "NIK", "id_str": "nik", "full_name": "NF-\u03baB-inducing kinase (MAP3K14)", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Constitutively degraded at rest; stabilised by receptor engagement, then activates IKK\u03b1.", "detail": "", "samhd1_effect": "" }, "x": -340.0, "y": -60.0, "z": 340.0 }, { "id": 133, "v": { "name": "IKK\u03b1", "id_str": "ikka", "full_name": "Inhibitor of \u03baB kinase alpha (CHUK) \u2014 the non-canonical catalytic subunit", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Phosphorylates p100 for partial proteasomal processing to p52 \u2014 a slower, NEMO-independent arm.", "detail": "", "samhd1_effect": "" }, "x": -400.0, "y": -120.0, "z": 300.0 }, { "id": 134, "v": { "name": "p52 : RelB", "id_str": "relb", "full_name": "Non-canonical NF-\u03baB heterodimer", "compartment": "nucleus", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Drives BAFF, CCL19/21 and lymphoid-organisation genes rather than the acute inflammatory set.", "detail": "", "samhd1_effect": "" }, "x": -460.0, "y": 40.0, "z": 20.0 }, { "id": 135, "v": { "name": "BAFF", "id_str": "baff", "full_name": "B-cell activating factor (TNFSF13B)", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "th17" ], "summary": "B-cell survival and differentiation factor; elevated across interferonopathies and autoimmune disease.", "detail": "", "samhd1_effect": "Amlexanox suppresses BAFF induction alongside type-I IFN production \u2014 one of the reasons the TBK1/IKK\u03b5 clamp is expected to reach further than JAK1 blockade alone." }, "x": -640.0, "y": 880.0, "z": 260.0 }, { "id": 136, "v": { "name": "NF-\u03baB target set", "id_str": "nfkb-targets", "full_name": "\u03baB-element gene set \u2014 NLRP3, IL1B, IL18, IL6, IL23A, TNF, CXCL8, NFKBIA, TNFAIP3", "compartment": "nucleus", "class": "complex", "evidence": "S", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb", "inflammasome" ], "summary": "One transcription factor, the entire priming layer: the inflammasome components, its substrates, the Th17-driving cytokine, and its own brakes.", "detail": "Reading the target list explains why \"NF-\u03baB primes NLRP3\" is doing so much work as a phrase. The same activation event supplies NLRP3 protein, pro-IL-1\u03b2 AND pro-IL-18 (the two inflammasome substrates), IL-23 (the Th17 driver), IL-6, TNF-\u03b1, and both of its own negative regulators. Signal 1 is not a permissive step; it builds the whole downstream apparatus.", "samhd1_effect": "SAMHD1 suppresses the NF-\u03baB pathway directly, so haploinsufficiency raises the resting level of every gene on this list at once. That is Brake 4 \u2014 and it is why Loop B and the Th17 arm are elevated at baseline rather than only after a trigger." }, "x": -240.0, "y": -40.0, "z": -260.0 }, { "id": 137, "v": { "name": "pro-IL-18", "id_str": "proil18", "full_name": "Inactive interleukin-18 precursor", "compartment": "cytosol", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "inflammasome", "nfkb", "ifn-gamma" ], "summary": "Unlike pro-IL-1\u03b2, it is constitutively present in many cells \u2014 so caspase-1 activation alone can release mature IL-18 fast.", "detail": "This asymmetry matters for the IFN-\u03b3 loop: IL-18 does not have to wait for signal 1, so a purely metabolic NLRP3 trigger can drive IFN-\u03b3 induction without any classical priming event.", "samhd1_effect": "" }, "x": 360.0, "y": -220.0, "z": 20.0 }, { "id": 138, "v": { "name": "CXCL8 / IL-8", "id_str": "cxcl8", "full_name": "Interleukin-8 \u2014 neutrophil chemoattractant", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "nfkb" ], "summary": "Canonical NF-\u03baB output and part of the ME/CFS cytokine panel measured in Arm 1.", "detail": "", "samhd1_effect": "" }, "x": -500.0, "y": 880.0, "z": 340.0 }, { "id": 139, "v": { "name": "NK / Th1 cell", "id_str": "responder-cell", "full_name": "Neighbouring NK cell or Th1 lymphocyte \u2014 the IFN-\u03b3 source", "compartment": "responder", "class": "cell", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "th17" ], "summary": "IFN-\u03b3 is made HERE, not in the cell whose mitochondria are failing. Loop C is paracrine by construction.", "detail": "NK cells respond fastest and need no antigen; Th1 cells sustain the response. Both read the same two signals \u2014 IL-18 through a MyD88 receptor and IL-12 through a STAT4 receptor \u2014 and neither alone is sufficient.", "samhd1_effect": "This is the step that is missing from the compressed chain. An inflammasome running constitutively in one cell recruits a second cell into the disease, and that second cell sends back a cytokine that damages the first one further." }, "x": -1120.0, "y": 960.0, "z": 180.0 }, { "id": 140, "v": { "name": "Th17 / ILC3 / \u03b3\u03b4 T", "id_str": "th17-cell", "full_name": "IL-17-producing lymphocyte populations", "compartment": "responder", "class": "cell", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17" ], "summary": "The IL-23-responsive compartment. In enthesitis the dominant producers are tissue-resident \u03b3\u03b4 T and ILC3, not circulating Th17.", "detail": "This distinction is clinically load-bearing: entheseal IL-17 comes largely from resident innate-like lymphocytes responding to IL-23, which is why the psoriatic arthritis arm can run without a classical autoantigen or autoantibody.", "samhd1_effect": "" }, "x": -980.0, "y": 800.0, "z": 300.0 }, { "id": 141, "v": { "name": "pDC", "id_str": "pdc", "full_name": "Plasmacytoid dendritic cell \u2014 the professional type-I interferon producer", "compartment": "responder", "class": "cell", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "tlr", "ifn-jak" ], "summary": "The cell that converts TLR7/9 ligation into an IFN-\u03b1 burst \u2014 orders of magnitude more type-I interferon per cell than any other blood leukocyte.", "detail": "Among the TLRs a pDC expresses essentially only TLR7 and TLR9, and it retains ligand in an early endosome long enough for the MyD88\u2013IRAK1\u2013IRF7 complex to assemble there. That retention, together with constitutively high resting IRF7, is why the same receptor gives NF-\u03baB cytokines in a macrophage and an interferon burst here \u2014 the difference is the cell, not the receptor. IRAK1 is the kinase step and it is already an atlas node (irak14, data/sensing.js); this is the cell that step happens in, not a second copy.", "samhd1_effect": "NOT demonstrated in a SAMHD1 system, and graded G for exactly that reason \u2014 it sits downstream of an S claim without inheriting its grade. What makes the cell worth drawing is arithmetic rather than a new mechanism: IRF7 is the node SAMHD1 physically restrains (Brake 1), and the pDC is where derepressed IRF7 has the largest per-cell interferon consequence. Whether pDCs contribute measurably to the tonic IFN-\u03b1 of this phenotype is a MEASUREMENT \u2014 pDC frequency together with per-cell IFN-\u03b1 \u2014 not something this model asserts." }, "x": -1180.0, "y": 1040.0, "z": -20.0 }, { "id": 142, "v": { "name": "IL-18R1 / IL-18RAP", "id_str": "il18r", "full_name": "Interleukin-18 receptor complex", "compartment": "responder", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "inflammasome" ], "summary": "An IL-1-family receptor: TIR domains, MyD88, IRAK \u2014 the same module TLRs use.", "detail": "Because IL-18 signals through MyD88, the inflammasome output reaches NF-\u03baB in the responder cell by exactly the route a pathogen would use. The cell cannot distinguish sterile metabolic inflammasome activity from infection.", "samhd1_effect": "" }, "x": -960.0, "y": 1080.0, "z": 60.0 }, { "id": 143, "v": { "name": "IL-18BP", "id_str": "il18bp", "full_name": "Interleukin-18 binding protein \u2014 the constitutive IL-18 decoy", "compartment": "extracellular", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "isg" ], "summary": "A high-affinity secreted decoy that neutralises free IL-18. Itself IFN-\u03b3-inducible \u2014 the loop builds its own brake.", "detail": "The clinically useful readout is not total IL-18 but FREE IL-18 \u2014 the fraction unbound by IL-18BP. Total IL-18 can look unremarkable while free IL-18 is high, which is the same measurement trap the concept note describes for serum cytokines generally. Recombinant IL-18BP (tadekinig alfa) exists as a therapeutic.", "samhd1_effect": "Worth measuring alongside free ISG15 in this framework: both are brakes that are induced by the very signal they oppose, and both are candidates for being present, engaged, and overwhelmed." }, "x": 220.0, "y": 1000.0, "z": 340.0 }, { "id": 144, "v": { "name": "IL-12 (p35/p40)", "id_str": "il12", "full_name": "Interleukin-12 \u2014 the Th1-polarising heterodimer", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "th17" ], "summary": "Made by activated myeloid cells. Shares its p40 subunit with IL-23 \u2014 which is why one antibody can hit both.", "detail": "The p40 sharing is the reason ustekinumab (anti-p40) suppresses the Th1 and Th17 arms together while anti-p19 agents spare IL-12. In a disease with both an IFN-\u03b3 arm and a Th17 arm, that choice is not neutral.", "samhd1_effect": "" }, "x": -300.0, "y": 960.0, "z": 260.0 }, { "id": 145, "v": { "name": "IL-12R\u03b21/\u03b22", "id_str": "il12r", "full_name": "Interleukin-12 receptor", "compartment": "responder", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma" ], "summary": "Signals through TYK2 and JAK2 \u2192 STAT4. The TYK2 dependence is why TYK2 inhibitors reach this arm.", "detail": "", "samhd1_effect": "" }, "x": -1240.0, "y": 1080.0, "z": 260.0 }, { "id": 146, "v": { "name": "STAT4", "id_str": "stat4", "full_name": "Signal transducer and activator of transcription 4", "compartment": "responder", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma" ], "summary": "The Th1 STAT. Induces T-bet, which is what actually licenses the IFNG locus.", "detail": "", "samhd1_effect": "" }, "x": -1180.0, "y": 880.0, "z": 40.0 }, { "id": 147, "v": { "name": "T-bet (TBX21)", "id_str": "tbet", "full_name": "T-box transcription factor 21 \u2014 master Th1 regulator", "compartment": "responder", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma" ], "summary": "Remodels the IFNG locus. Without it, IL-18 and IL-12 signalling produce no interferon-\u03b3.", "detail": "T-bet is the step that makes the two-signal requirement real: IL-18's NF-\u03baB arm cannot transactivate a closed locus, and IL-12's STAT4 arm is what opens it.", "samhd1_effect": "" }, "x": -1060.0, "y": 800.0, "z": 120.0 }, { "id": 148, "v": { "name": "STAT1 : STAT1 (GAF)", "id_str": "gaf", "full_name": "Gamma-activated factor \u2014 the STAT1 homodimer", "compartment": "cytosol", "class": "complex", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "ifn-jak" ], "summary": "A different dimer from ISGF3, reading a different element (GAS, not ISRE) \u2014 but drawing on the same STAT1 pool.", "detail": "Type-I and type-II interferon compete for STAT1. That shared dependency is why JAK1 inhibition dampens both arms, and why STAT1 abundance is a better readout of total interferon burden than either ligand alone.", "samhd1_effect": "" }, "x": 240.0, "y": 440.0, "z": -140.0 }, { "id": 149, "v": { "name": "CXCL9/10/11", "id_str": "cxcl9-11", "full_name": "Interferon-\u03b3-induced chemokines (MIG, IP-10, I-TAC)", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "isg" ], "summary": "CXCR3 ligands that recruit more Th1 and NK cells \u2014 the loop's amplification step at tissue level.", "detail": "", "samhd1_effect": "CXCL10 is one of the four assays the concept note directs workup toward (with IFN-\u03b1/\u03b2, free ISG15 and ISG scoring) precisely because it reports intracellular interferon activity when a standard cytokine panel reads normal." }, "x": 560.0, "y": 920.0, "z": -220.0 }, { "id": 150, "v": { "name": "CIITA \u2192 MHC-II", "id_str": "ciita", "full_name": "Class II transactivator and MHC class II induction", "compartment": "nucleus", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma" ], "summary": "IFN-\u03b3 turns non-professional cells into antigen presenters \u2014 how an innate loop acquires an adaptive audience.", "detail": "", "samhd1_effect": "" }, "x": -200.0, "y": 180.0, "z": -280.0 }, { "id": 151, "v": { "name": "NOS2 / iNOS", "id_str": "nos2", "full_name": "Inducible nitric oxide synthase", "compartment": "cytosol", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "ifn-gamma", "metabolic" ], "summary": "IFN-\u03b3 + NF-\u03baB output. NO nitrosylates and inhibits Complexes I and IV \u2014 an interferon-driven respiratory lesion.", "detail": "NOS2 induction is one of the most direct routes from a cytokine to a bioenergetic defect: nitric oxide competes with oxygen at cytochrome c oxidase and S-nitrosylates Complex I.", "samhd1_effect": "" }, "x": 400.0, "y": 260.0, "z": -300.0 }, { "id": 152, "v": { "name": "M1 polarisation", "id_str": "m1", "full_name": "Classically activated (M1) macrophage programme", "compartment": "cytosol", "class": "outcome", "evidence": "S", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "ifn-gamma", "metabolic", "mito" ], "summary": "IFN-\u03b3 locks macrophages into aerobic glycolysis with a broken TCA cycle, high mtROS, and succinate accumulation.", "detail": "M1 is where Loop C re-enters the mitochondrion. The programme itself raises mtROS and remodels the TCA cycle \u2014 so an interferon signal arriving from a neighbouring cell physically worsens the organelle damage that started the cascade. Succinate accumulation from the broken cycle stabilises HIF-1\u03b1 under normoxia, which is the Warburg shift already in this figure.", "samhd1_effect": "Samhd1-KO drives M1 skewing directly, and does so alongside \u0394\u03a8m collapse. The cell arrives at this state from two directions at once: its own genetic lesion, and the IFN-\u03b3 its neighbours send back." }, "x": 460.0, "y": 160.0, "z": -180.0 }, { "id": 153, "v": { "name": "IL-23R / IL-12R\u03b21", "id_str": "il23r", "full_name": "Interleukin-23 receptor complex", "compartment": "responder", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17" ], "summary": "JAK2/TYK2 \u2192 STAT3. IL23R variants are among the strongest genetic associations in psoriatic disease.", "detail": "", "samhd1_effect": "" }, "x": -1000.0, "y": 920.0, "z": 420.0 }, { "id": 154, "v": { "name": "STAT3", "id_str": "stat3", "full_name": "Signal transducer and activator of transcription 3", "compartment": "responder", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17" ], "summary": "The Th17 STAT, driven by IL-6 and IL-23. Induces ROR\u03b3t.", "detail": "", "samhd1_effect": "" }, "x": -1040.0, "y": 880.0, "z": 340.0 }, { "id": 155, "v": { "name": "ROR\u03b3t (RORC)", "id_str": "rorgt", "full_name": "Retinoic acid receptor-related orphan receptor gamma t", "compartment": "responder", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17" ], "summary": "Master Th17 transcription factor. IL-23 does not create Th17 cells so much as stabilise and license them.", "detail": "", "samhd1_effect": "" }, "x": -1090.0, "y": 830.0, "z": 270.0 }, { "id": 156, "v": { "name": "IL-17RA / RC", "id_str": "il17ra", "full_name": "Interleukin-17 receptor on the target tissue", "compartment": "membrane", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17" ], "summary": "Signals through ACT1 \u2192 TRAF6 \u2192 NF-\u03baB in fibroblasts, synoviocytes and keratinocytes.", "detail": "IL-17 is a weak cytokine alone and a potent one with TNF-\u03b1. The synergy is why enthesitis responds to blocking either arm and why the two appear together in every mechanistic account of psoriatic disease.", "samhd1_effect": "" }, "x": -80.0, "y": 620.0, "z": -440.0 }, { "id": 157, "v": { "name": "ACT1 (TRAF3IP2)", "id_str": "act1", "full_name": "NF-\u03baB activator 1 \u2014 the IL-17R adaptor", "compartment": "cytosol", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17", "nfkb" ], "summary": "U-box E3 that couples IL-17R to TRAF6 \u2192 NF-\u03baB \u2014 closing an IL-17 \u2192 NF-\u03baB \u2192 IL-23 feed-forward at tissue level.", "detail": "", "samhd1_effect": "" }, "x": -140.0, "y": 460.0, "z": -400.0 }, { "id": 158, "v": { "name": "IL-22 / GM-CSF", "id_str": "il22", "full_name": "Additional Th17-lineage effector cytokines", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "dendritic_cell", "cd4_tcell" ], "pathways": [ "th17" ], "summary": "Epithelial proliferation (IL-22) and myeloid recruitment (GM-CSF) \u2014 the rest of the Th17 output.", "detail": "", "samhd1_effect": "" }, "x": 340.0, "y": 960.0, "z": -400.0 }, { "id": 159, "v": { "name": "IL-18R \u2192 NF-\u03baB (Responder)", "id_str": "il18r-nfkb", "full_name": "Responder cell NF-\u03baB activation downstream of IL-18R", "compartment": "cytosol", "class": "tf", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell" ], "pathways": [ "ifn-gamma", "nfkb" ], "summary": "IL-18R MyD88-dependent NF-\u03baB transactivation inside responder lymphoid cells.", "detail": "IL-18 engagement of IL-18R\u03b1/\u03b2 recruits MyD88, IRAK4 and TRAF6, activating NF-\u03baB to drive co-transcription of IFN-\u03b3 and chemokines in NK/Th1 cells.", "samhd1_effect": "Second arm of the paracrine Loop C circuit." }, "x": -380.0, "y": 220.0, "z": 140.0 }, { "id": 160, "v": { "name": "Z-form nucleic acid", "id_str": "z-rna", "full_name": "Z-RNA / Z-DNA \u2014 left-handed duplex from repeat and ERV transcripts", "compartment": "cytosol", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath", "retro" ], "summary": "Left-handed duplex conformation favoured by alternating purine-pyrimidine repeats \u2014 abundant in ERV and SINE transcripts.", "detail": "Z-form is a conformation, not a sequence: the same molecule flips between B and Z depending on torsional strain, salt and sequence. That is why it works as a danger signal at all \u2014 the cell is reading a physical state that accumulates when repeat transcription runs unchecked, rather than a motif a virus could simply mutate away.", "samhd1_effect": "The substrate pool for this sensor is exactly what SAMHD1 haploinsufficiency raises. HERV and LINE-1 de-repression is already modelled in the retroelement layer; this is where those transcripts acquire a second way to be dangerous, independent of MDA5." }, "x": -180.0, "y": -400.0, "z": 460.0 }, { "id": 161, "v": { "name": "ZBP1", "id_str": "zbp1", "full_name": "Z-DNA binding protein 1 (DAI / DLM-1) \u2014 Z\u03b1-domain nucleic-acid sensor", "compartment": "cytosol", "class": "sensor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath", "retro" ], "summary": "Two Z\u03b1 domains read Z-form nucleic acid; two RHIM domains hand the signal to RIPK3. Itself an interferon-stimulated gene.", "detail": "ZBP1 is the only sensor in this atlas whose ligand is a CONFORMATION. Being an ISG makes it self-amplifying in an interferon-high state: the more interferon, the more sensor, and the sensor detects something the same interferon programme is failing to suppress.", "samhd1_effect": "Untested in SAMHD1 systems. The prediction is straightforward and worth measuring: ZBP1 protein should be elevated in A565T cells simply because it is an ISG, at the same time as its Z-form substrate rises from retroelement de-repression. If both are true, necroptotic priming is a phenotype nobody has looked for here.", "db_xrefs": "{\"uniprot\": \"Q9H171\", \"ensembl\": \"ENSG00000171806\", \"hgnc\": \"HGNC:30950\"}" }, "x": -80.0, "y": -460.0, "z": 360.0 }, { "id": 162, "v": { "name": "RIPK3", "id_str": "ripk3", "full_name": "Receptor-interacting serine/threonine kinase 3", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath" ], "summary": "RHIM-dependent amyloid-like assembly with ZBP1 or RIPK1; phosphorylates MLKL. The commitment step.", "detail": "RHIM\u2013RHIM interaction builds a genuine amyloid core, which is why necroptotic commitment is so hard to reverse once made \u2014 the same all-or-nothing polymer logic as MAVS filaments and ASC specks. This graph now has three of them.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"Q9Y572\", \"ensembl\": \"ENSG00000129465\", \"hgnc\": \"HGNC:10021\"}" }, "x": 120.0, "y": -560.0, "z": 220.0 }, { "id": 163, "v": { "name": "RIPK1", "id_str": "ripk1", "full_name": "Receptor-interacting serine/threonine kinase 1", "compartment": "cytosol", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath", "nfkb" ], "summary": "The three-way switch: scaffold for NF-\u03baB survival signalling, or substrate for caspase-8, or RHIM partner for necroptosis.", "detail": "Which of the three happens is decided by ubiquitin editing \u2014 the same LUBAC/A20/CYLD machinery already in the NF-\u03baB module. That makes RIPK1 a direct link between this arm and the ubiquitin control layer.", "samhd1_effect": "" }, "x": 20.0, "y": -520.0, "z": 280.0 }, { "id": 164, "v": { "name": "MLKL", "id_str": "mlkl", "full_name": "Mixed lineage kinase domain-like pseudokinase \u2014 the necroptotic executioner", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath" ], "summary": "Phosphorylated by RIPK3, then oligomerises and permeabilises the plasma membrane directly.", "detail": "A pseudokinase with no catalytic activity of its own \u2014 it is a pore, not an enzyme. Sub-lytic MLKL activity causes K\u207a efflux without killing the cell, which is enough to license NLRP3.", "samhd1_effect": "" }, "x": 220.0, "y": -580.0, "z": 150.0 }, { "id": 165, "v": { "name": "caspase-8 / FADD", "id_str": "casp8", "full_name": "Caspase-8 with FADD \u2014 the necroptosis brake", "compartment": "cytosol", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath" ], "summary": "Cleaves RIPK1 and RIPK3 to suppress necroptosis. Losing it does not stop death \u2014 it switches the mode.", "detail": "Caspase-8-null mice die embryonically, and deleting RIPK3 rescues them completely. The apoptotic machinery is not only an executioner; it is the thing holding the lytic pathway shut. That inversion is why blocking apoptosis pharmacologically can convert a silent death into an inflammatory one.", "samhd1_effect": "" }, "x": 0.0, "y": -620.0, "z": 120.0 }, { "id": 166, "v": { "name": "necroptosis", "id_str": "necroptosis", "full_name": "Caspase-independent lytic programmed cell death", "compartment": "cytosol", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "celldeath" ], "summary": "Membrane rupture with the cytosol intact \u2014 maximally immunogenic, and invisible to every caspase inhibitor.", "detail": "", "samhd1_effect": "The framework has a caspase-1 lytic route (pyroptosis) and now a caspase-INDEPENDENT one. Nothing in the ten-arm design touches this axis: MCC950 blocks NLRP3, IMSB301 blocks cGAS, and neither has any effect on RIPK3\u2013MLKL. If necroptosis contributes to the mtDNA released into the extracellular space, it is an unmeasured source of the ligand that keeps Loop A supplied." }, "x": 320.0, "y": -600.0, "z": 80.0 }, { "id": 167, "v": { "name": "PANoptosome", "id_str": "panoptosome", "full_name": "ZBP1-nucleated complex converging pyroptosis, apoptosis and necroptosis", "compartment": "cytosol", "class": "complex", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "celldeath", "inflammasome" ], "summary": "ZBP1 scaffolds NLRP3, ASC, caspase-1, caspase-8 and RIPK3 into one complex \u2014 the three death modes stop being separate.", "detail": "The practical consequence for this atlas is that the tidy separation between Loop B and the cell-death arm is a modelling convenience. Where a PANoptosome forms, ASC specks and RIPK3 filaments are the same event, and blocking one output redistributes flux to the others rather than stopping it.", "samhd1_effect": "" }, "x": 200.0, "y": -440.0, "z": 60.0 }, { "id": 168, "v": { "name": "LINE-1 locus", "id_str": "l1-locus", "full_name": "Long interspersed nuclear element 1 (L1HS) \u2014 the only autonomous human retrotransposon", "compartment": "nucleus", "class": "retro", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "genome" ], "summary": "~500 000 copies, ~17% of the genome, ~100 still retrotransposition-competent. 6 kb bicistronic unit with its own internal promoter.", "detail": "L1 encodes everything it needs: a 5\u2032UTR promoter, ORF1p (an RNA chaperone) and ORF2p (endonuclease + reverse transcriptase). Alu and SVA elements have no ORFs at all and hijack ORF2p in trans \u2014 which means silencing L1 silences the whole mobile fraction of the genome, and de-silencing it releases all of it.", "samhd1_effect": "" }, "x": -460.0, "y": 240.0, "z": -320.0 }, { "id": 169, "v": { "name": "Alu / SINE loci", "id_str": "alu-locus", "full_name": "Alu short interspersed nuclear elements", "compartment": "nucleus", "class": "retro", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "rlr-mavs" ], "summary": "~1.1 million copies, ~11% of the genome. Non-autonomous \u2014 mobilised in trans by L1 ORF2p.", "detail": "Alus matter here for a reason unrelated to mobility: inverted Alu pairs in 3\u2032UTRs fold into long duplex RNA. That duplex is the endogenous MDA5 ligand the cell must continuously suppress by editing.", "samhd1_effect": "" }, "x": -380.0, "y": -20.0, "z": -380.0 }, { "id": 170, "v": { "name": "HERV loci", "id_str": "herv-locus", "full_name": "Human endogenous retroviruses \u2014 LTR retroelements", "compartment": "nucleus", "class": "retro", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "~8% of the genome. Mostly ORF-dead, but transcriptionally reactivatable and immunogenic.", "detail": "HERV-K and HERV-W envelope proteins are direct TLR4 agonists, and HERV transcripts feed both TLR7/8 and the cytosolic dsRNA pool. Silenced by TRIM28/KAP1 with KRAB zinc-finger proteins rather than by HUSH.", "samhd1_effect": "" }, "x": -240.0, "y": 280.0, "z": -340.0 }, { "id": 171, "v": { "name": "L1 mRNA", "id_str": "l1-mrna", "full_name": "Bicistronic L1 transcript (ORF1 + ORF2)", "compartment": "nucleus", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "RNA Pol II transcript from the internal 5\u2032UTR promoter; exported and translated in the cytoplasm.", "detail": "", "samhd1_effect": "" }, "x": -280.0, "y": 80.0, "z": -340.0 }, { "id": 172, "v": { "name": "ORF1p", "id_str": "orf1p", "full_name": "L1 ORF1 protein \u2014 trimeric nucleic-acid chaperone", "compartment": "granule", "class": "retro", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Coats L1 RNA in a strong cis preference, so an L1 mRNA is mobilised by the proteins it encoded.", "detail": "", "samhd1_effect": "" }, "x": -580.0, "y": -270.0, "z": 300.0 }, { "id": 173, "v": { "name": "ORF2p", "id_str": "orf2p", "full_name": "L1 ORF2 protein \u2014 endonuclease + reverse transcriptase", "compartment": "cytosol", "class": "retro", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "genome" ], "summary": "The business end: an APE-like endonuclease that nicks genomic DNA and an RT that copies L1 RNA into it.", "detail": "ORF2p is translated at very low efficiency by an unconventional mechanism \u2014 the cell keeps it scarce because it is genuinely dangerous. Its reverse transcriptase is dNTP-dependent, which is exactly where SAMHD1 intervenes.", "samhd1_effect": "SAMHD1 restricts L1 by two routes at once: it starves ORF2p reverse transcriptase of dNTPs, and it promotes stress-granule formation that sequesters the L1 ribonucleoprotein. Both routes are lost together in haploinsufficiency \u2014 and the dNTP route is lost in the WRONG direction, because the pool goes UP by 40\u201360%." }, "x": -500.0, "y": -360.0, "z": 260.0 }, { "id": 174, "v": { "name": "L1 RNP", "id_str": "l1-rnp", "full_name": "L1 ribonucleoprotein particle (L1 RNA + ORF1p + ORF2p)", "compartment": "granule", "class": "retro", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "The transposition-competent intermediate. Must reach the nucleus to insert.", "detail": "", "samhd1_effect": "SAMHD1 promotes stress-granule formation that traps L1 RNPs out of circulation. This is a physical, non-enzymatic restriction mechanism \u2014 and it is regulated by SAMHD1 T592 phosphorylation, meaning the same phospho-switch that governs genome stability also governs retroelement restriction." }, "x": -620.0, "y": -190.0, "z": 280.0 }, { "id": 175, "v": { "name": "TPRT", "id_str": "tprt", "full_name": "Target-primed reverse transcription", "compartment": "nucleus", "class": "retro", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "genome" ], "summary": "ORF2p nicks genomic DNA at a TTAAAA-like consensus; the freed 3\u2032-OH primes reverse transcription in situ.", "detail": "The mechanism is the reason retrotransposition is inseparable from DNA damage: every insertion attempt begins with a deliberate nick in the genome, and most attempts abort, leaving the break behind.", "samhd1_effect": "" }, "x": -400.0, "y": -220.0, "z": -300.0 }, { "id": 176, "v": { "name": "new L1 insertion", "id_str": "l1-insertion", "full_name": "De novo retrotransposition event", "compartment": "nucleus", "class": "retro", "evidence": "I", "evidence_tier": "L1_in_silico", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "genome" ], "summary": "Usually 5\u2032-truncated and inert; occasionally disruptive, and always a source of structural variation.", "detail": "", "samhd1_effect": "Elevated dNTP pools support L1 reverse transcription, so retroelement mutagenic burden is one of the three pressures in the genomic-instability block alongside replication-error load and impaired homologous recombination." }, "x": -300.0, "y": -220.0, "z": -280.0 }, { "id": 177, "v": { "name": "L1 cDNA", "id_str": "l1-cdna", "full_name": "Cytosolic L1 reverse-transcription product (ssDNA / RNA:DNA hybrid)", "compartment": "cytosol", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "cgas-sting" ], "summary": "Aborted or cytoplasmic reverse transcription leaves DNA where DNA should not be \u2014 and cGAS reads it.", "detail": "This is the mechanistic bridge from retroelement biology to interferonopathy. In TREX1-deficient models, L1 cDNA accumulation is a demonstrated source of neuroinflammation; in senescence, L1 de-repression drives the age-associated interferon response. The same ligand class, three different diseases.", "samhd1_effect": "" }, "x": -380.0, "y": -240.0, "z": 180.0 }, { "id": 178, "v": { "name": "Alu inverted-repeat dsRNA", "id_str": "alu-dsrna", "full_name": "Duplex RNA formed by inverted Alu pairs in 3\u2032UTRs", "compartment": "cytosol", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "rlr-mavs" ], "summary": "The endogenous MDA5 ligand. Long, perfectly duplexed, abundant \u2014 and entirely self.", "detail": "The cell has no structural way to distinguish this from viral dsRNA. Its only defence is to chemically mark it: ADAR1 p150 deaminates adenosine to inosine, creating I:U mismatches that destabilise the duplex below the MDA5 filament-nucleation threshold. Lose the editing and self RNA becomes non-self.", "samhd1_effect": "" }, "x": -260.0, "y": -220.0, "z": 440.0 }, { "id": 179, "v": { "name": "HERV transcripts", "id_str": "herv-rna", "full_name": "Endogenous retroviral RNA and Env protein", "compartment": "cytosol", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "tlr" ], "summary": "Feeds the cytosolic dsRNA pool, TLR7/8 in endosomes, and TLR4 via Env protein.", "detail": "", "samhd1_effect": "" }, "x": -140.0, "y": -340.0, "z": 420.0 }, { "id": 180, "v": { "name": "HUSH complex", "id_str": "hush", "full_name": "Human silencing hub \u2014 TASOR + MPP8 + PPHLN1", "compartment": "nucleus", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Recognises young, intronless, long transcription units \u2014 the structural signature of a recent L1 insertion.", "detail": "HUSH is remarkable because it identifies retroelements by the SHAPE of the transcription unit rather than by sequence, which lets it silence insertions the genome has never seen before. It recruits MORC2 for chromatin compaction and SETDB1 to deposit H3K9me3.", "samhd1_effect": "" }, "x": -540.0, "y": 180.0, "z": -280.0 }, { "id": 181, "v": { "name": "MORC2", "id_str": "morc2", "full_name": "MORC family CW-type zinc finger 2 \u2014 ATP-dependent chromatin compactor", "compartment": "nucleus", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "The effector arm of HUSH: physically compacts chromatin over the target locus.", "detail": "", "samhd1_effect": "" }, "x": -480.0, "y": 300.0, "z": -240.0 }, { "id": 182, "v": { "name": "SETDB1", "id_str": "setdb1", "full_name": "SET domain bifurcated histone lysine methyltransferase 1", "compartment": "nucleus", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Deposits H3K9me3, the repressive mark that keeps L1 and HERV loci heterochromatic.", "detail": "", "samhd1_effect": "" }, "x": -580.0, "y": 100.0, "z": -320.0 }, { "id": 183, "v": { "name": "H3K9me3", "id_str": "h3k9me3", "full_name": "Trimethylated histone H3 lysine 9 \u2014 the repressive mark", "compartment": "nucleus", "class": "structure", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Read by HP1, propagated across the locus. The physical substrate of retroelement silence.", "detail": "", "samhd1_effect": "" }, "x": -520.0, "y": 240.0, "z": -360.0 }, { "id": 184, "v": { "name": "DNMT1 / UHRF1", "id_str": "dnmt1", "full_name": "Maintenance DNA methyltransferase and its targeting partner", "compartment": "nucleus", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Maintains CpG methylation of the L1 5\u2032UTR promoter through replication \u2014 the oldest defence layer.", "detail": "Global hypomethylation in cancer and in ageing de-represses L1 by exactly this route, which is why retroelement activity and genomic instability track together across so many conditions.", "samhd1_effect": "" }, "x": -600.0, "y": 200.0, "z": -180.0 }, { "id": 185, "v": { "name": "TRIM28 / KAP1", "id_str": "trim28", "full_name": "Tripartite motif 28 with KRAB zinc-finger proteins", "compartment": "nucleus", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "The LTR/HERV silencing arm: KRAB-ZFPs supply sequence specificity, TRIM28 recruits SETDB1.", "detail": "", "samhd1_effect": "" }, "x": -300.0, "y": 300.0, "z": -340.0 }, { "id": 186, "v": { "name": "ZAP / ZC3HAV1", "id_str": "zap", "full_name": "Zinc-finger antiviral protein", "compartment": "cytosol", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Binds CpG-dinucleotide-rich RNA and routes it to the exosome. Inhibits both L1 and Alu retrotransposition.", "detail": "ZAP works because the human genome is CpG-depleted while retroelement and viral RNAs are not \u2014 a compositional tell rather than a sequence motif.", "samhd1_effect": "" }, "x": -660.0, "y": -180.0, "z": 220.0 }, { "id": 187, "v": { "name": "MOV10", "id_str": "mov10", "full_name": "Moloney leukaemia virus 10 \u2014 RNA helicase", "compartment": "granule", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "Associates with L1 RNP and unwinds/destabilises it; an ISG, so interferon reinforces this layer.", "detail": "", "samhd1_effect": "" }, "x": -660.0, "y": -270.0, "z": 260.0 }, { "id": 188, "v": { "name": "OAS1-3", "id_str": "oas", "full_name": "2\u2032-5\u2032-oligoadenylate synthetases", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "isg", "retro" ], "summary": "dsRNA-activated; makes 2-5A to switch on RNase L. A parallel dsRNA-sensing arm to MDA5.", "detail": "", "samhd1_effect": "" }, "x": -460.0, "y": -300.0, "z": 400.0 }, { "id": 189, "v": { "name": "RNase L", "id_str": "rnasel", "full_name": "Ribonuclease L", "compartment": "cytosol", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "isg", "retro" ], "summary": "Cleaves single-stranded RNA indiscriminately once activated \u2014 including L1 and Alu transcripts.", "detail": "", "samhd1_effect": "" }, "x": -400.0, "y": -380.0, "z": 360.0 }, { "id": 190, "v": { "name": "ADAR1 p150", "id_str": "adar1", "full_name": "Adenosine deaminase acting on RNA 1, interferon-inducible isoform", "compartment": "cytosol", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "rlr-mavs", "isg" ], "summary": "A-to-I edits Alu duplex RNA, creating I:U mismatches that keep MDA5 below its activation threshold.", "detail": "ADAR1 is the reason self dsRNA is tolerated. Loss of ADAR1 editing is AGS6, and the resulting disease is entirely MDA5-dependent: deleting MDA5 rescues ADAR1-null mice. It is the cleanest demonstration in immunology that an autoinflammatory disease can be a failure of self-marking rather than a failure of sensing.", "samhd1_effect": "" }, "x": -120.0, "y": -260.0, "z": 460.0 }, { "id": 191, "v": { "name": "APOBEC3A/B", "id_str": "apobec3", "full_name": "Apolipoprotein B mRNA editing enzyme catalytic subunits 3A/3B", "compartment": "cytosol", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "genome" ], "summary": "Cytidine deaminases that hypermutate L1 cDNA (C\u2192U, read as G\u2192A) before it can integrate.", "detail": "The same enzymes are a major endogenous mutagen in cancer genomes \u2014 restriction and mutagenesis are the same activity pointed at different substrates.", "samhd1_effect": "" }, "x": -520.0, "y": -120.0, "z": 340.0 }, { "id": 192, "v": { "name": "TREX1", "id_str": "trex1", "full_name": "Three-prime repair exonuclease 1 (DNase III) \u2014 AGS1", "compartment": "cytosol", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "cgas-sting" ], "summary": "The dominant cytosolic 3\u2032\u21925\u2032 ssDNA exonuclease. Its job is to destroy L1 cDNA and other cytosolic DNA before cGAS finds it.", "detail": "TREX1 is the cleanest possible control experiment for this entire framework: remove one cytosolic DNA-clearing enzyme and you get lethal cGAS-driven autoimmunity in mice, and AGS1 in humans. Trex1-null disease is fully rescued by cGAS or STING deletion. SAMHD1 haploinsufficiency is the same logic applied one step upstream \u2014 instead of failing to clear the DNA, the cell fails to stop making it.", "samhd1_effect": "" }, "x": -400.0, "y": 100.0, "z": 440.0 }, { "id": 193, "v": { "name": "RNase H2 (A/B/C)", "id_str": "rnaseh2", "full_name": "Ribonuclease H2 heterotrimer \u2014 AGS2, AGS3, AGS4", "compartment": "nucleus", "class": "restrict", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro", "genome" ], "summary": "Removes ribonucleotides misincorporated into DNA and resolves RNA:DNA hybrids \u2014 including L1 TPRT intermediates.", "detail": "Three of the eight AGS loci are RNase H2 subunits. Their loss produces genome-embedded ribonucleotides, replication stress, and DNA fragments that reach the cytosol \u2014 arriving at cGAS by a different road than TREX1 loss but ending in the same interferon signature.", "samhd1_effect": "" }, "x": -280.0, "y": -260.0, "z": -180.0 }, { "id": 194, "v": { "name": "AGS gene family", "id_str": "ags-family", "full_name": "Aicardi-Gouti\u00e8res syndrome loci AGS1\u2013AGS8", "compartment": "nucleus", "class": "complex", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "retro" ], "summary": "TREX1 \u00b7 RNASEH2A/B/C \u00b7 SAMHD1 \u00b7 ADAR1 \u00b7 IFIH1 \u00b7 LSM11/RNU7-1 \u2014 every one a nucleic-acid metabolism gene.", "detail": "Read as a set, the AGS genes are a map of retroelement containment. TREX1 clears the cDNA; RNase H2 clears the hybrids; SAMHD1 starves the reverse transcriptase and sequesters the RNP; ADAR1 marks the duplex RNA as self; MDA5 is the sensor that reads the mark. Mutate any one and the same interferon signature appears. This is why SAMHD1 belongs in this family, and why a heterozygous SAMHD1 variant should be expected to produce an attenuated version of the same syndrome rather than something unrelated to it.", "samhd1_effect": "The heterozygous phenotype is the attenuated version: survival-compatible, adult-onset, moderate-amplitude, chronic rather than catastrophic \u2014 what the concept note names NACI." }, "x": -160.0, "y": 260.0, "z": -300.0 }, { "id": 195, "v": { "name": "micronuclei", "id_str": "micronucleus", "full_name": "Micronuclei from mis-segregated or damaged chromatin", "compartment": "nucleus", "class": "ligand", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "cd4_tcell", "dendritic_cell", "hsc" ], "pathways": [ "genome", "cgas-sting" ], "summary": "Rupture-prone envelopes that expose genomic DNA to cGAS \u2014 a nuclear source of Loop A ligand.", "detail": "", "samhd1_effect": "" }, "x": -180.0, "y": 340.0, "z": -220.0 }, { "id": 196, "v": { "name": "SAMHD1", "id_str": "samhd1", "full_name": "SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1", "compartment": "cytosol", "class": "restrict", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "samhd1" ], "summary": "Obligate homotetramer. dNTPase, replication-fork guardian, retroelement restrictor, innate-immune brake, mitochondrial stabiliser.", "detail": "The enzyme is allosterically gated: GTP/dGTP occupy allosteric site 1, the substrate dNTP occupies site 2, and only the fully loaded tetramer hydrolyses. Activity is further switched by CDK1/2\u2013cyclin A phosphorylation at Thr592 \u2014 phospho-SAMHD1 retains the genome-stability functions while the dephospho form carries the dNTPase restriction activity. That split is why any therapy that changes total SAMHD1 protein must be evaluated for BOTH functions, not just the one being targeted.\n\nDELIBERATELY NOT AN EDGE \u2014 the SAMHD1/NK-function relation. It is context-dependent with opposite signs, so no single signed edge can carry it, and this note exists so the next person to reach for one hits the same wall rather than picking a direction. In the TUMOUR microenvironment SAMHD1 RESTRAINS NK killing: selectively depleting tumour-associated SAMHD1 improves NK-mediated killing (Sun 2025), and SAMHD1-expressing breast tumours carry shorter time-to-progression via downregulated IL-12 signalling (Guti\u00e9rrez-Chamorro 2024). In acute RETROVIRAL infection it does the reverse: Samhd1-KO mice mount weaker NK, CD4+ and CD8+ responses (Barrett 2022) \u2014 and only male mice did so. Different cell of origin, different direction, and one of the three findings is sex-limited. Signs multiply along paths in this model, so an edge whose sign cannot be defended is worse than a documented gap.", "samhd1_effect": "Highly conserved down to zebrafish. Nuclear-predominant, but with functionally required cytosolic and mitochondrial pools. NOTE, and do not collapse this into an edge: the SAMHD1/NK-function relation is CONTEXT-DEPENDENT with opposite signs \u2014 SAMHD1 restrains NK killing in the tumour microenvironment (Sun 2025, Guti\u00e9rrez-Chamorro 2024) but supports NK/CD4/CD8 responses in acute retroviral infection, in male mice only (Barrett 2022). No signed edge is drawn for it, deliberately.", "db_xrefs": "{\"uniprot\": \"Q9Y3Z3\", \"ensembl\": \"ENSG00000101347\", \"hgnc\": \"HGNC:15925\", \"chembl\": \"CHEMBL4523507\", \"opentargets_ags\": 0.809}" }, "x": 40.0, "y": 20.0, "z": 220.0 }, { "id": 197, "v": { "name": "p.A565T", "id_str": "a565t", "full_name": "SAMHD1 c.1693G>A (p.Ala565Thr), NM_015474.3 \u2014 rs779491090", "compartment": "cytosol", "class": "outcome", "evidence": "S", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "samhd1" ], "summary": "Heterozygous missense at the extreme C-terminal boundary of the phosphohydrolase HD domain \u2014 27 residues from the T592 regulatory hinge.", "detail": "Introducing a polar, hydroxyl-bearing threonine at 565 warps the allosteric pocket walls of site 2 and destabilises the C-terminal regulatory lobe. The only direct functional data \u2014 Schneider, LMU Munich 2022 \u2014 showed 2.4\u00d7 reduced protein stability at equal mRNA in LN-18 and THP-1, but ONLY in homozygous/complete-loss models. Heterozygous cells were never tested. gnomAD v4 AF \u2248 1.1\u00d710\u207b\u2075.", "samhd1_effect": "The interpretive constraint is clinical, and it is the honest part of this framework: the observed course is survival to middle age without AGS, with symptomatic improvement during acute viral illness. Both are inconsistent with complete dNTPase loss and consistent with ~40\u201360% residual activity \u2014 one functional allele. Enough to prevent AGS5, not enough to prevent a sustained low-grade interferonopathy. Because SAMHD1 is an obligate homotetramer, HD-domain missense variants can additionally poison wild-type tetramers, so real activity may sit below 50%." }, "x": -60.0, "y": 100.0, "z": 300.0 }, { "id": 198, "v": { "name": "p-SAMHD1 (T592)", "id_str": "samhd1-t592", "full_name": "Thr592-phosphorylated SAMHD1 \u2014 CDK1/2\u2013cyclin A substrate", "compartment": "nucleus", "class": "restrict", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "samhd1", "genome" ], "summary": "The phospho-switch that partitions SAMHD1 between its dNTPase and its genome-stability roles.", "detail": "Phosphorylation at T592 also regulates LINE-1 restriction, tying the retroelement and genome-stability arms to the same residue.", "samhd1_effect": "The p-T592/total-SAMHD1 RATIO \u2014 not total protein \u2014 is proposed as a therapeutic monitoring biomarker. It is the readout that would catch amlexanox starving the genome-stability arm while it improves inflammation." }, "x": -260.0, "y": 160.0, "z": -180.0 }, { "id": 199, "v": { "name": "SAMHD1 (mitochondrial pool)", "id_str": "samhd1-mito", "full_name": "Mitochondrion-localised SAMHD1", "compartment": "mitochondrion", "class": "restrict", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "samhd1", "mito" ], "summary": "Diaz-Griffero's group showed SAMHD1 must be present INSIDE the mitochondrial compartment to prevent \u0394\u03a8m collapse and mtDNA release.", "detail": "This finding matters because it makes the mitochondrial arm a direct, local SAMHD1 function rather than a downstream consequence of cytosolic dNTP excess.", "samhd1_effect": "" }, "x": 400.0, "y": 120.0, "z": 360.0 }, { "id": 200, "v": { "name": "cytosolic dNTP pool", "id_str": "dntp-pool", "full_name": "Cytosolic deoxynucleoside triphosphate pool (dATP, dCTP, dGTP, dTTP)", "compartment": "cytosol", "class": "metabolite", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "samhd1", "metabolic", "genome", "retro" ], "summary": "Elevated 40\u201360% by dNTPase failure, with a disproportionate dGTP skew. The single upstream quantity from which four streams descend.", "detail": "Four streams descend from this one number:\n PURPLE \u2014 PNC1/PNC2 overload \u2192 POLG stalling \u2192 ox-mtDNA \u2192 NLRP3 (Loop B)\n BLUE \u2014 mtDNA escape via VDAC1 \u2192 cGAS (Loop A bridge)\n RED \u2014 IFN-I \u2192 JAK-STAT \u2192 ISGs \u2192 mitophagy block, ETC suppression\n GOLD \u2014 dG catabolism \u2192 uric acid \u2192 MSU crystals \u2192 NLRP3 (second Loop B input)", "samhd1_effect": "Measured by LC-MS/MS. This is the first-line Arm 1 readout, and the cheapest decisive experiment in the programme: a 40\u201360% elevation in primary heterozygous cells would establish that haploinsufficiency alone perturbs the pool, which no published work has yet shown." }, "x": 180.0, "y": 100.0, "z": 440.0 }, { "id": 201, "v": { "name": "stalled replication fork", "id_str": "fork", "full_name": "Stalled or reversed DNA replication fork", "compartment": "nucleus", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "genome" ], "summary": "SAMHD1 acts at stalled forks to prevent interferon induction \u2014 a nuclear, dNTPase-independent function.", "detail": "Coquel et al. showed SAMHD1 recruits MRE11 to degrade nascent DNA at stalled forks in a controlled way. Without it, the fork collapses instead, and the resulting single-stranded DNA fragments are released into the cytosol where cGAS binds them. This is interferon induction with no mitochondrion and no retroelement involved.", "samhd1_effect": "" }, "x": -440.0, "y": -120.0, "z": -240.0 }, { "id": 202, "v": { "name": "MRE11", "id_str": "mre11", "full_name": "Meiotic recombination 11 \u2014 MRN complex nuclease", "compartment": "nucleus", "class": "enzyme", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "genome" ], "summary": "Recruited by SAMHD1 for controlled nascent-strand degradation at stalled forks.", "detail": "", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"P49959\", \"ensembl\": \"ENSG00000020922\", \"hgnc\": \"HGNC:7230\"}" }, "x": -580.0, "y": -140.0, "z": -220.0 }, { "id": 203, "v": { "name": "CtIP", "id_str": "ctip", "full_name": "CtBP-interacting protein (RBBP8) \u2014 end-resection initiator", "compartment": "nucleus", "class": "enzyme", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "genome" ], "summary": "SAMHD1 recruits CtIP to double-strand breaks to initiate resection for homologous recombination.", "detail": "This is a scaffolding function entirely independent of dNTPase activity \u2014 which is why the genome-stability arm can fail even when residual enzymatic activity looks adequate.", "samhd1_effect": "", "db_xrefs": "{\"uniprot\": \"Q99708\", \"ensembl\": \"ENSG00000101773\", \"hgnc\": \"HGNC:9888\"}" }, "x": -520.0, "y": -60.0, "z": -300.0 }, { "id": 204, "v": { "name": "DNA double-strand break", "id_str": "dsb", "full_name": "DSB requiring homologous recombination or NHEJ", "compartment": "nucleus", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "genome" ], "summary": "Repair choice here determines whether the cell keeps its genome or accumulates rearrangements.", "detail": "", "samhd1_effect": "" }, "x": -480.0, "y": -200.0, "z": -180.0 }, { "id": 205, "v": { "name": "R-loops", "id_str": "rloop", "full_name": "RNA:DNA hybrid with a displaced single DNA strand", "compartment": "nucleus", "class": "structure", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "genome", "retro" ], "summary": "SAMHD1 prevents R-loop formation; accumulation drives transcription\u2013replication conflict and breaks.", "detail": "Quantified by S9.6 immunofluorescence \u2014 a primary readout in the study and a safety signal in Arm 5, where amlexanox may worsen it by suppressing IRF3-driven SAMHD1 transcription.", "samhd1_effect": "" }, "x": -380.0, "y": -180.0, "z": -160.0 }, { "id": 206, "v": { "name": "cytosolic ssDNA fragments", "id_str": "ssdna", "full_name": "Single-stranded DNA released from collapsed forks and resected breaks", "compartment": "cytosol", "class": "ligand", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "genome", "cgas-sting" ], "summary": "The genomic contribution to the cGAS ligand pool \u2014 parallel to the mitochondrial and retroelement routes.", "detail": "The Arm 7 vs Arm 8 comparison is designed to size this stream: if cGAS inhibition (Arm 8) suppresses ISGs more deeply than VDAC1 blockade (Arm 7), a non-mitochondrial DNA source \u2014 this one \u2014 is contributing meaningfully.", "samhd1_effect": "" }, "x": -260.0, "y": -120.0, "z": 180.0 }, { "id": 207, "v": { "name": "genomic instability", "id_str": "genomic-instability", "full_name": "Cumulative replication error, HR failure and retroelement mutagenesis", "compartment": "nucleus", "class": "outcome", "evidence": "S", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "genome", "clinical" ], "summary": "Three converging pressures: elevated dNTP replication error load, impaired HR, and retroelement insertion burden.", "detail": "", "samhd1_effect": "Translates into a cancer-surveillance rationale rather than a claim of present malignancy: prostate (BIK + SAMHD1 co-segregating susceptibility), colorectal (heterozygous SAMHD1 mutations), and haematological risk from SAMHD1's canonical tumour-suppressor role in myeloid and lymphoid lineages. It is also the reason the framework treats amlexanox as a tradeoff rather than a free anti-inflammatory." }, "x": -340.0, "y": -300.0, "z": -240.0 }, { "id": 208, "v": { "name": "SAMHD1 heterotetramer (2xWT + 2xA565T)", "id_str": "samhd1-heterotetramer", "full_name": "Heterozygous mixed homotetramer ensemble (Binomial 37.5% 2:2 stoichiometry)", "compartment": "cytosol", "class": "complex", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "pathways": [ "samhd1", "metabolic" ], "summary": "In A565T heterozygotes, SAMHD1 forms mixed 2xWT + 2xA565T tetramers retaining ~50% dNTPase but uncoupling cooperative PTM switches.", "detail": "Binomial distribution predicts 37.5% of complexes assemble as 2:2 heterotetramers. They maintain dosage-limited basal dNTPase activity (ipTM=0.81) but suffer severe allosteric uncoupling at the phosphorylated C-terminal hinge.", "samhd1_effect": "The structural basis for heterozygous haploinsufficiency with 100% phenotypic penetrance.", "kinetics": "{\"tetramer_Kd_uM\": 2.4, \"hill_coefficient\": 2.1, \"mixed_tetramer_fraction\": 0.375}" }, "x": 20.0, "y": 100.0, "z": -80.0 }, { "id": 209, "v": { "name": "peptide\u2013MHC", "id_str": "apc-antigen", "full_name": "Antigen-presenting cell displaying peptide on MHC", "compartment": "extracellular", "class": "complex", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The physiological input. Everything in this arm is a response to an antigen a T cell has recognised.", "detail": "The paper drives this arm two ways \u2014 tetanus toxoid\u2013loaded antigen-presenting cells, and EBV gp350 \u2014 in addition to the antibody-bead shortcut of CD3/CD28 ligation. That matters for interpretation: TRAILshort suppresses responses to REAL antigen, not only to artificial receptor crosslinking.", "samhd1_effect": "" }, "x": -1280.0, "y": 1240.0, "z": 200.0 }, { "id": 210, "v": { "name": "TCR\u2013CD3", "id_str": "tcr-cd3", "full_name": "T cell receptor \u03b1\u03b2 heterodimer in complex with CD3\u03b3\u03b5/\u03b4\u03b5/\u03b6\u03b6", "compartment": "responder", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The antigen receptor itself. It has no catalytic activity of its own \u2014 all its signalling is borrowed from associated kinases.", "detail": "The \u03b1\u03b2 heterodimer does the recognising but carries no enzymatic function; the signalling is done by the CD3 chains bolted to it, whose cytoplasmic tails hold the ITAMs. This is why the pathway can be switched off by a phosphatase without the receptor being blocked, removed, or its antigen displaced \u2014 which is exactly what TRAILshort does.", "samhd1_effect": "" }, "x": -1180.0, "y": 1120.0, "z": 360.0 }, { "id": 211, "v": { "name": "Lck", "id_str": "lck", "full_name": "Lymphocyte-specific protein tyrosine kinase", "compartment": "responder", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The Src-family kinase that phosphorylates the CD3\u03b6 ITAMs \u2014 the first catalytic event of the cascade.", "detail": "Lck writes the phosphates that ZAP-70 later reads. Because SHP-1 is a phosphatase, the TRAILshort lesion is best understood as an ERASER acting on what Lck WRITES: the two enzymes contest the same residues, and the balance between them sets whether the receptor signals at all.", "samhd1_effect": "" }, "x": -1280.0, "y": 1100.0, "z": 340.0 }, { "id": 212, "v": { "name": "CD28", "id_str": "cd28", "full_name": "CD28 costimulatory receptor", "compartment": "responder", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "Signal 2. Antigen recognition alone drives anergy; costimulation is what makes it activation.", "detail": "The two-signal requirement is the T-cell analogue of the priming/activation split that governs NLRP3 in Loop B \u2014 a recurring shape in immunology, where a dangerous effector programme needs two independent permissions. Every CD3/CD28 bead experiment in this paper is supplying both.", "samhd1_effect": "" }, "x": -1120.0, "y": 1160.0, "z": 300.0 }, { "id": 213, "v": { "name": "TRAIL (full length)", "id_str": "trail-fl", "full_name": "TNFSF10 \u2014 the trimerising parent ligand", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The functional counterpart. It trimerises DR4/DR5 and kills; TRAILshort occupies the same receptor and does not.", "detail": "Full-length TRAIL is expressed on activated T and NK cells and used to kill virally infected and transformed targets while sparing healthy tissue. Trimerised, it clusters death receptors, recruits FADD and pro-caspase-8 into a DISC, and drives apoptosis \u2014 and can additionally signal necroptosis via RIPK1/RIPK3, or non-apoptotic NF-\u03baB and MAPK/p38 in TRAIL-resistant tumour cells. THAT is the route to NF-\u03baB in this arm, and it belongs to the parent ligand, not to TRAILshort. TRAILshort is the dominant negative of all of it.", "samhd1_effect": "" }, "x": -1440.0, "y": 1040.0, "z": 240.0 }, { "id": 214, "v": { "name": "TRAILshort", "id_str": "trailshort", "full_name": "TRAIL splice variant lacking cysteine 230 \u2014 dominant-negative, non-trimerising", "compartment": "extracellular", "class": "cytokine", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "A non-trimerising TRAIL splice variant that silences T cells by phosphatase recruitment rather than by killing them.", "detail": "TRAILshort lacks Cys230 and therefore cannot form the trimer that clusters death receptors. It is presented on cell surfaces AND packaged into extracellular vesicles, which is what lets it act on bystander cells rather than only on the cell that made it \u2014 the reason it appears in this compartment at all. Unbiased GEO enrichment finds TRAILshort RNA elevated across COVID-19, Zika, tuberculosis, myelofibrosis, multiple neoplasms, Crohn disease and SLE; prior work adds HIV. The common thread across that list is immune dysfunction, which is the observation the mechanistic work set out to explain.", "samhd1_effect": "NO established SAMHD1 link. This arm is imported context for the T-cell attrition phenotype, not a consequence of A565T. Treat it as a candidate modifier to be tested, not as part of the variant cascade." }, "x": -1360.0, "y": 1120.0, "z": 300.0 }, { "id": 215, "v": { "name": "DR5 (TRAIL-R2)", "id_str": "dr5", "full_name": "TNFRSF10B \u2014 death receptor 5", "compartment": "responder", "class": "receptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The receptor TRAILshort binds preferentially. Engaged WITHOUT clustering, it becomes a phosphatase-docking site instead of a death platform.", "detail": "Full-length TRAIL trimerises DR5, recruits FADD and pro-caspase-8 into a DISC, and drives apoptosis, necroptosis or NF-\u03baB. TRAILshort occupies the same receptor and does none of that: DR5 pull-downs after TRAILshort treatment show no FADD, no caspase-8 and no RIPK1, whereas super-killer TRAIL shows all three. The receptor is the same; the signal is entirely different. DR5-KO abolishes TRAILshort signalling, which is what makes DR5 the required junction rather than an incidental binding partner.", "samhd1_effect": "" }, "x": -1200.0, "y": 1040.0, "z": 440.0 }, { "id": 216, "v": { "name": "SHP-1 (PTPN6)", "id_str": "shp1", "full_name": "Src homology region 2 domain\u2013containing phosphatase 1", "compartment": "responder", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The actual effector. Recruited to TRAILshort-bound DR5, autophosphorylated at Y536, and it switches the TCR off from the inside.", "detail": "SHP-1 sits autoinhibited at rest through an intramolecular N-terminal SH2\u2013phosphatase interaction, and is released on engagement by ITIM- or ITSM-bearing receptors, autophosphorylating at Y536. TNFR-family receptors including Fas were already known to recruit it; this paper establishes DR5 doing so in human T cells. Mass spectrometry of TRAILshort-Fc pull-downs identified ZAP-70, CD3\u03b6 and SHP-1 as uniquely TRAILshort-interacting. Both TRAILshort peptide and TRAILshort EVs induce SHP-1 pY536.", "samhd1_effect": "" }, "x": -1260.0, "y": 960.0, "z": 380.0 }, { "id": 217, "v": { "name": "CD3\u03b6", "id_str": "cd3z", "full_name": "CD247 \u2014 the TCR \u03b6-chain carrying the ITAMs", "compartment": "responder", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The ITAM platform ZAP-70 docks onto. TRAILshort does not remove it \u2014 it breaks the association.", "detail": "Lck phosphorylates the CD3\u03b6 ITAMs on TCR engagement, and the doubly phosphorylated ITAM is what the ZAP-70 tandem SH2 module binds. Because SHP-1 strips the activating phosphates, the ZAP-70\u2013CD3\u03b6 interaction is lost rather than the components being degraded \u2014 which is why the effect is reversible on SHP-1 removal.", "samhd1_effect": "" }, "x": -1080.0, "y": 1080.0, "z": 400.0 }, { "id": 218, "v": { "name": "ZAP-70", "id_str": "zap70", "full_name": "Zeta-chain-associated protein kinase 70", "compartment": "responder", "class": "kinase", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The dephosphorylation target (Y319). Everything downstream in the TCR cascade falls behind it.", "detail": "ZAP-70 is the first kinase of the TCR cascade proper, and pY319 is the site the paper tracks by both immunoblot and flow cytometry. CD3/CD28 ligation normally raises p\u2013ZAP-70, p-LAT and p-PLC\u03b3 together; TRAILshort pretreatment diminishes all three. TRAILshort alone, without CD3/CD28 stimulation, does nothing \u2014 this is a brake on activation, not a stimulus in its own right.", "samhd1_effect": "" }, "x": -1140.0, "y": 980.0, "z": 460.0 }, { "id": 219, "v": { "name": "LAT", "id_str": "lat", "full_name": "Linker for activation of T cells", "compartment": "responder", "class": "adaptor", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The scaffold ZAP-70 phosphorylates at Y191/Y220, and the point where one lost phosphosite becomes a whole lost programme.", "detail": "", "samhd1_effect": "" }, "x": -1080.0, "y": 900.0, "z": 480.0 }, { "id": 220, "v": { "name": "PLC\u03b31", "id_str": "plcg1", "full_name": "Phospholipase C gamma 1", "compartment": "responder", "class": "enzyme", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "Recruited to phospho-LAT and activated at Y783. Its output is the calcium and DAG arm that licenses the effector programme.", "detail": "PLC\u03b31 is where reduced proximal phosphorylation turns into reduced function: less IP3/DAG means less calcium flux and less PKC\u03b8 activity, and downstream the paper measures exactly that as fewer CD69+CD40L+ cells, less proliferation, and less IFN-\u03b3. Note that NFAT \u2014 the classic calcium-dependent readout \u2014 falls only SLIGHTLY, which is why the authors locate the lesion proximally rather than at the transcription factor.", "samhd1_effect": "" }, "x": -1070.0, "y": 800.0, "z": 400.0 }, { "id": 221, "v": { "name": "CD69", "id_str": "cd69", "full_name": "Early T-cell activation marker", "compartment": "responder", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The earliest surface readout of successful activation \u2014 up within hours, and reduced by TRAILshort.", "detail": "Measured by flow cytometry as the CD69+CD40L+CD4+ fraction responding to EBV gp350. TRAILshort EVs reduce it; SHP-1 inhibition raises it back. As an early marker it reports on the proximal block directly, without the confound of the days-long proliferation readouts.", "samhd1_effect": "" }, "x": -940.0, "y": 860.0, "z": 360.0 }, { "id": 222, "v": { "name": "CD40L", "id_str": "cd40l", "full_name": "CD154 \u2014 T-cell help delivered to B cells and APCs", "compartment": "responder", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "The molecule by which an activated T cell licenses B cells and dendritic cells. Losing it silences help, not just killing.", "detail": "This is the output that makes TRAILshort a TOLERANCE mechanism rather than merely a cytotoxicity block. A T cell that cannot express CD40L cannot license the antigen-presenting cell that activated it, so the suppression propagates outward into the humoral and dendritic compartments as well.", "samhd1_effect": "" }, "x": -880.0, "y": 980.0, "z": 360.0 }, { "id": 223, "v": { "name": "clonal proliferation", "id_str": "tcell-prolif", "full_name": "Antigen-driven T-cell expansion", "compartment": "responder", "class": "effector", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr" ], "summary": "Measured by CFSE dilution. Suppressed by TRAILshort EVs across a Transwell, and restored by SHP-1 inhibition.", "detail": "The Transwell design is the load-bearing control: TRAILshort-expressing MEFs suppress proliferation of T cells they never touch. That establishes the effect as EV-mediated and soluble, which is what licenses placing TRAILshort in the extracellular compartment acting on a bystander cell.", "samhd1_effect": "" }, "x": -980.0, "y": 1060.0, "z": 360.0 }, { "id": 224, "v": { "name": "CD19 CAR-T", "id_str": "car-t", "full_name": "CD19-directed chimeric antigen receptor T cells", "compartment": "extracellular", "class": "drug", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr", "drugs" ], "summary": "A therapy this arm predicts will underperform in a TRAILshort-high tumour \u2014 and did, in humanised mice.", "detail": "CAR-T cells signal through the same CD3\u03b6 ITAMs as a native TCR, which is precisely why they are vulnerable here: the CAR changes what the cell recognises, not how it transduces. TRAILshort MEFs impaired CD19 CAR-T\u2013mediated control of lymphoma in vivo. If that generalises, TRAILshort level is a candidate predictive biomarker for CAR-T failure, and anti-TRAILshort a candidate combination partner.", "samhd1_effect": "" }, "x": -1580.0, "y": 1040.0, "z": 280.0 }, { "id": 225, "v": { "name": "anti-TRAILshort", "id_str": "anti-trailshort", "full_name": "TRAILshort-neutralising monoclonal antibody", "compartment": "extracellular", "class": "drug", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr", "drugs" ], "summary": "Neutralising the ligand restores T-cell function \u2014 the \"release the brake\" direction.", "detail": "In co-cultures of patient T cells with autologous TRAILshort-expressing B cells, anti-TRAILshort antibody raised IFN-\u03b3 secretion across marginal zone lymphoma, DLBCL and florid lymphoid hyperplasia (P < 0.05). In humanised mice TRAILshort promoted persistence of transformed MEFs and L428 cells and antagonised CD19-directed CAR-T activity, so neutralisation is the proposed route to restoring it.", "samhd1_effect": "" }, "x": -1500.0, "y": 1180.0, "z": 400.0 }, { "id": 226, "v": { "name": "NSC-87877", "id_str": "nsc87877", "full_name": "Small-molecule SHP-1 inhibitor", "compartment": "responder", "class": "drug", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "cd4_tcell", "cd8_tcell", "nk_cell", "monocyte" ], "pathways": [ "tcr", "drugs" ], "summary": "Blocks the phosphatase rather than the ligand. Works, but only modestly \u2014 and the gap is informative.", "detail": "SHP-1 inhibition raised CD69+CD40L+CD4+ frequency and IFN-\u03b3 in TRAILshort-treated T cells responding to EBV antigen, and restored proliferation against TRAILshort EVs. But pharmacological inhibition reversed the ZAP-70 phosphorylation defect far less completely than CRISPR KO or siRNA knockdown of SHP-1 did. The authors attribute this to the limited potency and specificity of the compound \u2014 so read this node as validating the TARGET, not as endorsing this molecule.", "samhd1_effect": "" }, "x": -1400.0, "y": 920.0, "z": 440.0 }, { "id": 227, "v": { "name": "upadacitinib", "id_str": "upadacitinib", "full_name": "JAK1-selective inhibitor \u2014 Arm 2 (and the shared brake in Arms 4, 6)", "compartment": "cytosol", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Arrests IFNAR signal transduction at JAK1 \u2014 the only node in this framework with in-human response data.", "detail": "Short-course JAK1 inhibition resolves the inflammatory arm of this disease almost completely while leaving core fatigue and metabolic dysfunction largely intact. That split is the empirical basis for the two-arm (and later three-arm) model: a JAK\u2013STAT-driven inflammatory component, and a metabolic/bioenergetic component that requires upstream rescue.", "samhd1_effect": "Predicted NOT to change: dNTP pools, R-loops, autophagy flux, p-TBK1(Ser172), ANKIB1 protein, IL-1\u03b2, or ASC speck burden. Everything it fails to move is a map of the disease it does not treat.", "db_xrefs": "{\"chembl\": \"CHEMBL3989938\", \"drugbank\": \"DB12399\"}" }, "x": -280.0, "y": 600.0, "z": 60.0 }, { "id": 228, "v": { "name": "brepocitinib / TYK2i", "id_str": "brepocitinib", "full_name": "Dual JAK1/TYK2 or selective TYK2 inhibitors", "compartment": "cytosol", "class": "drug", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Alternative to JAK1-only blockade; adds IL-12/IL-23 coverage relevant to the Th17/psoriatic arm.", "detail": "", "samhd1_effect": "" }, "x": 80.0, "y": 600.0, "z": 280.0 }, { "id": 229, "v": { "name": "amlexanox", "id_str": "amlexanox", "full_name": "TBK1/IKK\u03b5 inhibitor \u2014 Arm 5 (and Arm 6 in combination)", "compartment": "cytosol", "class": "drug", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Cuts interferon production at source rather than blocking its reception. Also an established metabolic agent.", "detail": "Because TBK1/IKK\u03b5 is the master switch linking cGAS\u2013STING to IRF3/7 transactivation, this clamp suppresses IFN production upstream of everything JAK inhibition touches. Reilly et al. showed the same target improves obesity-related metabolic dysfunction, so it lands on both arms at once.", "samhd1_effect": "CRITICAL TRADEOFF, and the most important safety claim in the study: by suppressing IRF3/7-mediated SAMHD1 transcription, amlexanox may reduce total SAMHD1 protein in a cell that is ALREADY haploinsufficient. As total protein falls, the p-T592/total ratio shifts toward dNTPase-active tetramers while functionally starving the phospho-dependent genome-stability roles. If DR-GFP efficiency or S9.6 R-loop burden WORSENS in Arm 5 despite inflammatory improvement, that is direct human evidence of a genome-stability/immune-control tradeoff \u2014 and an argument for pulsed rather than continuous dosing.", "db_xrefs": "{\"chembl\": \"CHEMBL442\", \"drugbank\": \"DB00223\"}" }, "x": 20.0, "y": 360.0, "z": 160.0 }, { "id": 230, "v": { "name": "poly-ICLC (Hiltonol)", "id_str": "polyiclc", "full_name": "TLR3 agonist \u2014 Arm 3 (Arm 4 with JAK1 shielding)", "compartment": "endosome", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "The \"upward\" direction: drive IRF3 to INDUCE more SAMHD1 protein in a haploinsufficient cell.", "detail": "Arm 3 alone is expected to improve genomic-stability endpoints while provoking an interferon surge. Arm 4 adds upadacitinib to test whether the genome-stability gain can be uncoupled from the surge. Dosing follows the published ME/CFS poly I:C PBMC protocol of Che et al. 2025 (0.2\u201320 \u00b5g/ml, 12\u201348 h).", "samhd1_effect": "" }, "x": -200.0, "y": -220.0, "z": 600.0 }, { "id": 231, "v": { "name": "VBIT-4", "id_str": "vbit4", "full_name": "VDAC1 oligomerisation inhibitor \u2014 Arm 7 (outer mitochondrial membrane)", "compartment": "mitochondrion", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Closes the macropore. In SAMHD1-KO monocytes it prevents mtDNA release and FULLY abolishes the spontaneous ISG response.", "detail": "Dose constraint is non-negotiable: above ~10 \u00b5M VBIT-4 produces VDAC1-INDEPENDENT membrane disruption, so the arm runs a strict 5 \u00b5M ceiling with PI/annexin-V viability gating at every timepoint. ISG suppression at non-cytotoxic concentrations is required for the result to mean anything.", "samhd1_effect": "" }, "x": 800.0, "y": 160.0, "z": 340.0 }, { "id": 232, "v": { "name": "IMSB301", "id_str": "imsb301", "full_name": "Oral selective cGAS inhibitor \u2014 Arm 8 (cytosolic sensor)", "compartment": "cytosol", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Intercepts cytosolic DNA AFTER mitochondrial egress. Blind to the ox-mtDNA/NLRP3 arm by construction.", "detail": "Predicted outcome is the single highest-value result in Axis 3: ISG and IFN normalised, while IL-1\u03b2, ASC specks and caspase-1 p20 stay UNCHANGED. With Arm 9's mirror-image profile, that pair is the definitive Loop A/B independence matrix in primary human heterozygous cells.", "samhd1_effect": "" }, "x": 320.0, "y": 0.0, "z": 580.0 }, { "id": 233, "v": { "name": "MCC950", "id_str": "mcc950", "full_name": "NLRP3 inflammasome inhibitor \u2014 Arm 9 (cytosolic sensor)", "compartment": "cytosol", "class": "drug", "evidence": "G", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Binds the NACHT-domain Walker B motif, blocking ATPase-driven assembly downstream of BOTH ox-mtDNA and MSU inputs.", "detail": "Predicted mirror image of Arm 8: IL-1\u03b2, IL-18, ASC specks and caspase-1 p20 normalised; ISG signature unchanged. Residual IL-1\u03b2 despite confirmed absence of ASC specks would implicate a caspase-1-independent maturation route \u2014 which points at allopurinol as an adjunct.", "samhd1_effect": "" }, "x": 220.0, "y": -240.0, "z": 160.0 }, { "id": 234, "v": { "name": "PLP / vitamin B6", "id_str": "plp", "full_name": "Pyridoxal 5\u2032-phosphate \u2014 SLC25A33 (PNC1) transport inhibitor, Arm 10 (inner membrane)", "compartment": "mitochondrion", "class": "drug", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "The only arm upstream of BOTH NLRP3 and VDAC1 \u2014 and clinically available over the counter.", "detail": "The bifurcating prediction is what makes this arm worth running:\n Outcome A \u2014 Loop B suppressed, Loop A intact: the two loops are independently gated, and VDAC1 oligomerisation is driven by existing mtROS tone rather than by PNC1 substrate flux.\n Outcome B \u2014 both suppressed: PNC1-driven mtROS is the dominant upstream driver, and the therapeutic target hierarchy shifts to the inner membrane.\n Null \u2014 neither: heterozygous dNTP excess is below the SLC25A33 overload threshold, meaning this arm needs near-complete dNTPase loss to engage. Equally informative, and it defines the haploinsufficiency threshold.\n\nThe class has a positive control now. Liu 2026 blocked mitochondrial dNTP transport pharmacologically and abolished NLRP3 hyperactivation in macrophages from Samhd1-deficient mice AND from obese human donors \u2014 the rescue experiment that anchors Loop B. That validates the TARGET, not this compound: PLP itself remains graded I here, because nobody has run pyridoxal 5\u2032-phosphate against a SAMHD1-haploinsufficient cell.", "samhd1_effect": "" }, "x": 340.0, "y": 160.0, "z": 120.0 }, { "id": 235, "v": { "name": "allopurinol", "id_str": "allopurinol", "full_name": "Xanthine oxidase inhibitor \u2014 candidate adjunct, not a current arm", "compartment": "cytosol", "class": "drug", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "Would cut the GOLD stream at urate production if MSU crystals prove to be a real third NLRP3 input.", "detail": "", "samhd1_effect": "" }, "x": 40.0, "y": -320.0, "z": 560.0 }, { "id": 236, "v": { "name": "ABE8e-YA base editor", "id_str": "abe8e", "full_name": "Adenine base editor for A\u00b7T \u2192 G\u00b7C reversion of c.1693G>A", "compartment": "nucleus", "class": "drug", "evidence": "I", "evidence_tier": "L3_cell_line", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs" ], "summary": "The curative horizon: a clean transition mutation is a premier base-editing candidate, with no double-strand break required.", "detail": "", "samhd1_effect": "" }, "x": -200.0, "y": 200.0, "z": 60.0 }, { "id": 237, "v": { "name": "Ara-C (Ara-CTP)", "id_str": "arac", "full_name": "Cytarabine triphosphate (Ara-CTP) \u2014 nucleoside analogue chemotherapy", "compartment": "cytosol", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs", "genome" ], "summary": "SAMHD1 hydrolyzes and inactivates Ara-CTP; haploinsufficiency causes marked hypersensitivity and clinical chemotherapy toxicity.", "detail": "Schneider et al. (Nature Medicine 2017) and Herold et al. (2017) demonstrated that SAMHD1 is the primary cellular triphosphohydrolase degrading Ara-CTP. Defective tetramer assembly prevents drug inactivation, creating synthetic lethality in AML/hematological malignancies but severe host toxicity under standard dosing.", "samhd1_effect": "" }, "x": -120.0, "y": 160.0, "z": 360.0 }, { "id": 238, "v": { "name": "gemcitabine (dFdCTP)", "id_str": "gemcitabine", "full_name": "Gemcitabine triphosphate (dFdCTP) \u2014 cytidine analogue chemotherapy", "compartment": "cytosol", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "monocyte", "macrophage", "microglia", "cd4_tcell" ], "pathways": [ "drugs", "genome" ], "summary": "Substrate of SAMHD1 catalytic inactivation; defective tetramer assembly impairs drug hydrolysis, enhancing cytotoxic stalling.", "detail": "", "samhd1_effect": "" }, "x": -40.0, "y": 180.0, "z": 400.0 }, { "id": 239, "v": { "name": "NACI", "id_str": "naci", "full_name": "Non-Acute Chronic Interferonopathy \u2014 the proposed diagnostic category", "compartment": "extracellular", "class": "outcome", "evidence": "I", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Tonic, source-driven interferon activation with no flare-remit cyclicity and a seronegative cytokine profile.", "detail": "Distinguished from AGS, SAVI and CANDLE by kinetics and biomarkers rather than by signalling architecture: non-acute (persistently engaged, not episodic), chronic (sustained over decades, progressive rather than episodic), and acting through intracellular ISG induction rather than elevated serum cytokines. That last property is the clinically actionable part \u2014 it predicts that standard cytokine panels will read normal in active multi-system disease, and it redirects workup toward IFN-\u03b1/\u03b2, free ISG15, CXCL10 and ISG scoring.", "samhd1_effect": "Proposed as a descriptive category for this patient's pattern, explicitly NOT an established clinical entity. It requires independent validation before use outside the concept note." }, "x": 0.0, "y": -960.0, "z": 320.0 }, { "id": 240, "v": { "name": "ME/CFS", "id_str": "mecfs", "full_name": "Myalgic encephalomyelitis / chronic fatigue syndrome", "compartment": "extracellular", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Multi-generational, concordant phenotype, with age at onset falling in each successive generation.", "detail": "Heightened innate immunity, mitochondrial dysfunction, lipid oxidation and a Warburg shift are all documented in ME/CFS cohorts independently. SAMHD1 haploinsufficiency is proposed as a genetic driver of that convergent interferon\u2013mitochondrial phenotype in a subset \u2014 not as an explanation for all of ME/CFS. Falling age at onset across generations is consistent with apparent anticipation, plausibly from cumulative genomic instability or telomere attrition.", "samhd1_effect": "" }, "x": -320.0, "y": -1000.0, "z": 120.0 }, { "id": 241, "v": { "name": "PEM / fatigue", "id_str": "pem", "full_name": "Post-exertional malaise and core fatigue \u2014 the JAK-refractory residual", "compartment": "extracellular", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Reduced OXPHOS, impaired ATP generation, metabolic shifts worsening post-exertion \u2014 and largely refractory to JAK inhibition.", "detail": "", "samhd1_effect": "" }, "x": -460.0, "y": -980.0, "z": 320.0 }, { "id": 242, "v": { "name": "psoriatic arthritis", "id_str": "psa", "full_name": "Enthesitis-predominant psoriatic arthritis", "compartment": "extracellular", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "IL-23 \u2192 Th17 \u2192 IL-17A/TNF-\u03b1 at tendon\u2013bone and fascial insertions.", "detail": "The distinction matters: PsA is established at the diagnosis level, whereas SAMHD1-to-PsA causality remains a mechanistic hypothesis pending specialist review and cell-based confirmation.", "samhd1_effect": "" }, "x": 300.0, "y": -1000.0, "z": -20.0 }, { "id": 243, "v": { "name": "metabolic interferonopathy", "id_str": "steatosis", "full_name": "Hepatic steatosis, android adiposity, insulin resistance", "compartment": "extracellular", "class": "outcome", "evidence": "S", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Diet-refractory steatosis, pancreatic fatty infiltration and android-pattern central adiposity.", "detail": "Two independent drivers converge here. IRF7 \u2192 MCP-1 in visceral adipocytes gives the distribution (android, with no subcutaneous lower-body accumulation). The NLRP3/IL-1\u03b2 arm gives the hepatic insulin resistance \u2014 and SAMHD1-null animals develop steatohepatitis with no diet challenge at all, which is why this phenotype is modelled as immune-driven rather than as a caloric-balance problem.", "samhd1_effect": "" }, "x": 520.0, "y": -960.0, "z": 220.0 }, { "id": 244, "v": { "name": "immunodeficiency", "id_str": "immunodef", "full_name": "Progressive T-cell attrition with recurrent infection", "compartment": "extracellular", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Impaired intrinsic antiviral restriction + chronic antigenic load + interferon-driven lymphocyte attrition.", "detail": "", "samhd1_effect": "" }, "x": -560.0, "y": -960.0, "z": 20.0 }, { "id": 245, "v": { "name": "connective tissue failure", "id_str": "connective", "full_name": "Fascial, ligamentous and enthesial structural failure", "compartment": "extracellular", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Tonic IFN-\u03b3 \u2192 STAT1 antagonises TGF-\u03b2/Smad3 collagen-I transcription while upregulating MMP-1/MMP-3.", "detail": "", "samhd1_effect": "" }, "x": 100.0, "y": -1000.0, "z": -360.0 }, { "id": 246, "v": { "name": "dysautonomia / SFN", "id_str": "dysautonomia", "full_name": "Autonomic dysregulation via small-fibre neuropathy", "compartment": "extracellular", "class": "outcome", "evidence": "G", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Chronic tonic type-I IFN drives progressive injury to intraepidermal autonomic nerve fibres.", "detail": "", "samhd1_effect": "" }, "x": 460.0, "y": -980.0, "z": -300.0 }, { "id": 247, "v": { "name": "cancer surveillance", "id_str": "cancer-risk", "full_name": "Elevated malignancy risk from cumulative genomic instability", "compartment": "extracellular", "class": "outcome", "evidence": "S", "evidence_tier": "L6_human_clinical", "cell_context": [ "systemic_immune", "cns_neuro", "cardiovascular", "hepatic", "musculoskeletal" ], "pathways": [ "clinical" ], "summary": "Prostate (BIK + SAMHD1 co-segregating), colorectal (heterozygous SAMHD1) and haematological lineages.", "detail": "Framed as a surveillance rationale, not a claim of present malignancy \u2014 and as the reason IRF3\u2192SAMHD1 signalling should not be blunted too aggressively. SAMHD1 is a canonical tumour suppressor in myeloid and lymphoid lineages, so structural uncoupling drives replication stress in exactly the compartments this disease already inflames.", "samhd1_effect": "" }, "x": -200.0, "y": -980.0, "z": -420.0 }, { "id": 248, "v": { "name": "tadekinig alfa", "id_str": "tadekinig-alfa", "full_name": "Recombinant human IL-18-binding protein (rhIL-18BP)", "compartment": "extracellular", "class": "drug", "evidence": "S", "evidence_tier": "L4_primary_human", "cell_context": [ "systemic_immune", "monocyte", "macrophage" ], "pathways": [ "drugs", "ifn-gamma" ], "summary": "High-affinity soluble decoy receptor neutralizing circulating IL-18 to extinguish Loop C paracrine signaling.", "detail": "Tadekinig alfa binds IL-18 with picomolar affinity (Kd ~400 pM), preventing receptor engagement and blocking downstream NK/Th1 IFN-\u03b3 release.", "samhd1_effect": "Direct therapeutic interrupter of Loop C in SAMHD1-driven interferonopathies and systemic autoinflammation.", "db_xrefs": "{\"drugbank\": \"DB12845\"}" }, "x": -450.0, "y": 120.0, "z": 100.0 } ] }, { "edges": [ { "id": 1, "s": 1, "t": 2, "v": { "interaction": "produce", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "A", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "ATP + GTP \u2192 2\u20323\u2032-cGAMP", "detail": "" } }, { "id": 2, "s": 2, "t": 3, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "A", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "binds CDN pocket, closes lid", "detail": "" } }, { "id": 3, "s": 3, "t": 4, "v": { "interaction": "translocate", "sign": "+", "interaction_type": "compartment_translocation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", 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"vic_cardiac", "cd4_tcell" ], "label": "mito dsRNA escape (stressor S5)", "detail": "" } }, { "id": 10, "s": 7, "t": 6, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "tunes filament nucleation", "detail": "" } }, { "id": 11, "s": 6, "t": 10, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "CARD\u2013CARD prion-like seeding", "detail": "" } }, { "id": 12, "s": 5, "t": 10, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "CARD\u2013CARD seeding", "detail": "" } }, { "id": 13, "s": 6, "t": 11, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "peroxisomal platform \u2014 fast, IFN-independent ISGs", "detail": "" } }, { "id": 14, "s": 10, "t": 12, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 15, "s": 10, "t": 13, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 16, "s": 11, "t": 12, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 17, "s": 12, "t": 27, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "K63-Ub scaffolding", "detail": "" } }, { "id": 18, "s": 12, "t": 28, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 19, "s": 13, "t": 31, 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"v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "surface, MAL-dependent", "detail": "" } }, { "id": 23, "s": 15, "t": 21, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 24, "s": 16, "t": 21, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 25, "s": 21, "t": 22, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Myddosome assembly", "detail": "" } }, { "id": 26, "s": 22, "t": 13, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 27, "s": 22, "t": 30, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "IRAK1 \u2192 IRF7 (pDC burst)", "detail": "" } }, { "id": 28, "s": 17, "t": 18, "v": { "interaction": "bind", "sign": "+", "interaction_type": "allosteric_binding", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "condenses self-DNA into nuclease-resistant aggregates", "detail": "" } }, { "id": 29, "s": 18, "t": 16, "v": { "interaction": "sense", "sign": "+", "interaction_type": "nucleic_acid_sensing", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "the conversion step \u2014 self-DNA alone is NOT a TLR9 agonist, the complex is", "detail": "" } }, { "id": 30, "s": 20, "t": 12, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 31, "s": 20, "t": 13, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 32, "s": 23, "t": 24, "v": { "interaction": "produce", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "assembles K11-linked chains", "detail": "" } }, { "id": 33, "s": 24, "t": 3, "v": { "interaction": "ubiq", "sign": "+", "interaction_type": "ubiquitin_conjugation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "substrate 1 \u2014 primes STING", "detail": "" } }, { "id": 34, "s": 24, "t": 20, "v": { "interaction": "ubiq", "sign": "+", "interaction_type": "ubiquitin_conjugation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "substrate 2 \u2014 primes TRIF", "detail": "" } }, { "id": 35, "s": 24, "t": 26, "v": { "interaction": "ubiq", "sign": "+", "interaction_type": "ubiquitin_conjugation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "substrate 3 \u2014 primes NEMO", "detail": "" } }, { "id": 36, "s": 24, "t": 25, "v": { "interaction": "ubiq", "sign": "+", "interaction_type": "ubiquitin_conjugation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "substrate 4 \u2014 primes OPTN", "detail": "" } }, { "id": 37, "s": 24, "t": 23, "v": { "interaction": "ubiq", "sign": "+", "interaction_type": "ubiquitin_conjugation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "substrate 5 \u2014 AUTO-ubiquitination \u2192 proteasomal self-destruction", "detail": "" } }, { "id": 38, "s": 25, "t": 27, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "ankib1", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "OPTN recruits TBK1 to the scaffold", "detail": "" } }, { "id": 39, "s": 27, "t": 29, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "A", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Ser386/396 \u2192 dimerisation", "detail": "", "db_scores": "{\"string_combined\": 0.999, \"string_experimental\": 0.927, \"string_database\": 0.9}" } }, { "id": 40, "s": 27, "t": 30, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "", "db_scores": "{\"string_combined\": 0.992, \"string_experimental\": 0.331, \"string_database\": 0.9}" } }, { "id": 41, "s": 28, "t": 30, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "irf7", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "dominant IRF7 kinase \u2014 blocked by SAMHD1 in health", "detail": "" } }, { "id": 42, "s": 28, "t": 29, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 43, "s": 26, "t": 31, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "ubiquitin-chain-dependent IKK activation", "detail": "" } }, { "id": 44, "s": 31, "t": 32, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Ser32/36 \u2192 K48-Ub \u2192 proteasome", "detail": "" } }, { "id": 45, "s": 32, "t": 33, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", 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204, "t": 195, "v": { "interaction": "produce", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 345, "s": 29, "t": 196, "v": { "interaction": "produce", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "IRF3 induces SAMHD1 transcription \u2014 the \"upward\" therapeutic direction (Arms 3\u20134)", "detail": "" } }, { "id": 346, "s": 197, "t": 208, "v": { "interaction": "produce", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "label": "Assembles into 2:2 mixed tetramers", "detail": "" } }, { "id": 347, "s": 208, "t": 200, "v": { "interaction": "inhibit", "sign": "-", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "ipsc" ], "label": "Preserves partial ~50% dNTP depletion", "detail": "" } }, { "id": 348, "s": 209, "t": 210, "v": { "interaction": "bind", "sign": "+", "interaction_type": "allosteric_binding", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "peptide\u2013MHC engagement \u2014 signal 1", "detail": "" } }, { "id": 349, "s": 210, "t": 211, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "receptor engagement brings Lck to the CD3 tails", "detail": "" } }, { "id": 350, "s": 211, "t": 217, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "phosphorylates the CD3\u03b6 ITAMs \u2014 the phosphates SHP-1 later removes", "detail": "" } }, { "id": 351, "s": 212, "t": 223, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "signal 2 \u2014 without costimulation, antigen recognition drives anergy rather than activation", "detail": "" } }, { "id": 352, "s": 213, "t": 215, "v": { "interaction": "bind", "sign": "+", "interaction_type": "allosteric_binding", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "trimerises DR5 \u2192 DISC \u2192 apoptosis, necroptosis, or non-apoptotic NF-\u03baB/p38", "detail": "The signalling TRAILshort displaces. Both ligands occupy the same receptor; only this one clusters it." } }, { "id": 353, "s": 214, "t": 213, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "dominant negative \u2014 blocks TRAIL-mediated apoptosis in producing AND bystander cells", "detail": "" } }, { "id": 354, "s": 214, "t": 215, "v": { "interaction": "bind", "sign": "+", "interaction_type": "allosteric_binding", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "binds DR5 preferentially \u2014 but cannot trimerise, so the receptor never clusters", "detail": "DR5-KO cells lose TRAILshort signalling entirely, establishing this as the required junction. The absence of clustering is the whole mechanism: an occupied but unclustered DR5 recruits a phosphatase instead of a death-inducing signalling complex." } }, { "id": 355, "s": 215, "t": 216, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "recruits SHP-1 and drives autophosphorylation at Y536", "detail": "" } }, { "id": 356, "s": 217, "t": 218, "v": { "interaction": "bind", "sign": "+", "interaction_type": "allosteric_binding", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "phospho-ITAMs dock the ZAP-70 tandem SH2 module \u2014 the association TRAILshort disrupts", "detail": "" } }, { "id": 357, "s": 216, "t": 218, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "dephosphorylates ZAP-70 at Y319", "detail": "The sign-negative step, and the one the whole arm turns on. CRISPR KO or siRNA of SHP-1 reverses it cleanly; the small-molecule inhibitor only partially." } }, { "id": 358, "s": 218, "t": 219, "v": { "interaction": "phos", "sign": "+", "interaction_type": "kinase_phosphorylation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "phosphorylates LAT at Y191/Y220", "detail": "" } }, { "id": 359, "s": 219, "t": 220, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "phospho-LAT recruits and activates PLC\u03b31 (pY783)", "detail": "" } }, { "id": 360, "s": 220, "t": 139, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "proximal TCR output \u2014 CD69/CD40L upregulation, proliferation, cytokine production", "detail": "This is the edge that joins the TCR arm to Loop C. Follow the signs from TRAILshort and the product is negative: the atlas therefore DERIVES a damping of the paracrine IFN-\u03b3 source rather than asserting it." } }, { "id": 361, "s": 220, "t": 221, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "early activation marker \u2014 CD69+CD40L+CD4+ fraction falls under TRAILshort", "detail": "" } }, { "id": 362, "s": 220, "t": 222, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "T-cell help \u2014 the output that makes this tolerance rather than only cytotoxicity loss", "detail": "" } }, { "id": 363, "s": 220, "t": 223, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "clonal expansion, by CFSE dilution \u2014 suppressed across a Transwell by TRAILshort EVs", "detail": "" } }, { "id": 364, "s": 214, "t": 224, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "antagonises CD19-directed CAR-T control of lymphoma in humanised mice", "detail": "CAR-T cells transduce through the same CD3\u03b6 ITAMs as a native TCR, so a phosphatase lesion at ZAP-70 reaches them unchanged. The CAR alters recognition, not transduction." } }, { "id": 365, "s": 225, "t": 214, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "neutralises the ligand \u2014 restores IFN-\u03b3 in patient B-cell malignancy co-cultures", "detail": "" } }, { "id": 366, "s": 226, "t": 216, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "SHP-1 inhibition \u2014 partial rescue of p\u2013ZAP-70, fuller rescue of CD69/CD40L and IFN-\u03b3", "detail": "" } }, { "id": 367, "s": 227, "t": 90, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arm 2 \u2014 JAK1-selective", "detail": "" } }, { "id": 368, "s": 228, "t": 91, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "dual JAK1/TYK2", "detail": "" } }, { "id": 369, "s": 229, "t": 27, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arm 5 \u2014 cuts IFN production at source", "detail": "" } }, { "id": 370, "s": 229, "t": 28, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 371, "s": 229, "t": 196, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "TRADEOFF \u2014 suppressing IRF3 lowers SAMHD1 transcription in an already haploinsufficient cell", "detail": "" } }, { "id": 372, "s": 230, "t": 14, "v": { "interaction": "activate", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arms 3\u20134 \u2014 agonist, the \"upward\" direction", "detail": "" } }, { "id": 373, "s": 231, "t": 35, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arm 7 \u2014 outer membrane, \u22645 \u00b5M ceiling", "detail": "" } }, { "id": 374, "s": 232, "t": 1, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arm 8 \u2014 cytosolic sensor", "detail": "" } }, { "id": 375, "s": 233, "t": 111, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arm 9 \u2014 NACHT Walker B motif", "detail": "" } }, { "id": 376, "s": 234, "t": 45, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Arm 10 \u2014 inner membrane, upstream of BOTH loops", "detail": "" } }, { "id": 377, "s": 235, "t": 124, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "candidate adjunct if the GOLD stream is real", "detail": "" } }, { "id": 378, "s": 236, "t": 197, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "A\u00b7T \u2192 G\u00b7C reversion to wild type", "detail": "" } }, { "id": 379, "s": 196, "t": 237, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "hydrolyzes Ara-CTP; haploinsufficiency causes hypersensitivity", "detail": "" } }, { "id": 380, "s": 196, "t": 238, "v": { "interaction": "inhibit", "sign": "+", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "hydrolyzes dFdCTP; loss enhances cytotoxicity", "detail": "" } }, { "id": 381, "s": 78, "t": 239, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "tonic, moderate-amplitude, source-driven", "detail": "" } }, { "id": 382, "s": 105, "t": 239, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "intracellular ISG induction with flat serum cytokines", "detail": "" } }, { "id": 383, "s": 64, "t": 241, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "the JAK-refractory bioenergetic residual", "detail": "" } }, { "id": 384, "s": 64, "t": 240, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 385, "s": 239, "t": 240, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "I", "evidence_tier": "L1_in_silico", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 386, "s": 85, "t": 242, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "enthesitis at tendon\u2013bone insertions", "detail": "" } }, { "id": 387, "s": 85, "t": 245, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 388, "s": 80, "t": 245, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "STAT1 antagonises TGF-\u03b2/Smad3; MMP-1/3 up", "detail": "" } }, { "id": 389, "s": 86, "t": 243, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "visceral adipocyte inflammation \u2192 android distribution", "detail": "" } }, { "id": 390, "s": 118, "t": 243, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "JAK-resistant hepatic insulin resistance", "detail": "" } }, { "id": 391, "s": 63, "t": 243, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "Warburg shift", "detail": "" } }, { "id": 392, "s": 78, "t": 244, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "IFN-mediated lymphocyte attrition", "detail": "" } }, { "id": 393, "s": 78, "t": 246, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "G", "evidence_tier": "L3_cell_line", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "small-fibre neuropathy", "detail": "" } }, { "id": 394, "s": 207, "t": 247, "v": { "interaction": "drive", "sign": "+", "interaction_type": "catalytic_activation", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "", "cell_context": [ "monocyte", "macrophage", "microglia", "vic_cardiac", "cd4_tcell" ], "label": "", "detail": "" } }, { "id": 395, "s": 248, "t": 119, "v": { "interaction": "inhibit", "sign": "-", "interaction_type": "allosteric_suppression", "evidence": "S", "evidence_tier": "L4_primary_human", "loop": "C", "cell_context": [ "systemic_immune" ], "label": "Neutralizes free IL-18", "detail": "" } } ] }, { "status": [ { "error": "", "success": true } ] } ]