{"gene":"IL6ST","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1992,"finding":"GP130 (IL6ST) is a membrane glycoprotein that associates with the IL-6 receptor after ligand binding to potentiate the cytokine response; it functions as the signal-transducing component of the IL-6 receptor complex.","method":"Chromosomal localization and gene characterization studies; functional receptor association assays","journal":"Somatic cell and molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — foundational characterization with functional receptor association, replicated across multiple subsequent studies confirming signal transduction role","pmids":["1475713"],"is_preprint":false},{"year":1995,"finding":"The active IL6ST gene is located at chromosome band 5q11; a nontranscribed pseudogene exists at chromosome band 17p11.","method":"Chromosomal localization by fluorescence in situ hybridization and somatic cell genetics","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping experiment, single lab but clear result distinguishing active gene from pseudogene","pmids":["7736792"],"is_preprint":false},{"year":2008,"finding":"Structure-guided mutagenesis of gp130 identified amino acid residues in the extracellular domain (particularly in the cytokine-binding domain) that, when mutated, increase binding affinity to the IL-6/sIL-6R complex. A triple mutein (T102Y/Q113F/N114L) showed additive improvement in binding affinity and selective inhibition of IL-6 trans-signaling without affecting classic signaling, demonstrating species specificity of these interactions.","method":"3D structural analysis of gp130 in complex with IL-6 and sIL-6R, NMR analysis of membrane-proximal domain, site-directed mutagenesis, in vitro cell proliferation assays, acute phase gene expression assays, mouse model of acute inflammation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided mutagenesis combined with in vitro functional assays and in vivo validation, multiple orthogonal methods in one study","pmids":["18650419"],"is_preprint":false},{"year":2011,"finding":"Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling via sIL-6R but, under conditions of molar excess of sIL-6R over IL-6, can also trap free IL-6 into IL-6·sIL-6R·sgp130 ternary complexes, thereby inhibiting classic signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, identifying the colon as a prominent target of IL-6 trans-signaling.","method":"Quantitative binding studies, cell proliferation inhibition assays, comparison with anti-IL-6R antibody tocilizumab, in vivo mouse experiments with sgp130Fc","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of signaling complexes, in vivo validation, multiple orthogonal methods, mechanistically defines the selectivity of sgp130 inhibition","pmids":["21990364"],"is_preprint":false},{"year":2014,"finding":"Alternative intronic polyadenylation in intron 10 of the gp130 (IL6ST) transcript generates a novel soluble isoform, sgp130-E10 (70–80 kDa). The sgp130-E10 protein binds to the IL-6/sIL-6R complex but not to IL-6 alone, and specifically inhibits IL-6 trans-signaling.","method":"Molecular cloning, expression in human PBMCs, recombinant protein production as Fc-fusion, binding assays, IL-6 trans-signaling inhibition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic identification of novel isoform with functional validation using binding and signaling assays, in vitro reconstitution","pmids":["24973212"],"is_preprint":false},{"year":2017,"finding":"A homozygous missense mutation in IL6ST (p.N404Y) causes loss of IL-6, IL-11, IL-27, and OSM signaling through GP130 while largely preserving LIF signaling, demonstrating that the N404 residue is selectively required for a subset of GP130 cytokine responses.","method":"Patient genetic analysis, functional signaling assays in patient-derived cells, cytokine stimulation experiments","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function variant in human patient with functional validation across multiple cytokines, replicated in subsequent studies","pmids":["28747427"],"is_preprint":false},{"year":2007,"finding":"A non-conservative polymorphism in gp130 (Gly148Arg) reduces cellular proliferation and STAT3 phosphorylation in response to gp130 stimulation, demonstrating that this residue influences GP130 signaling efficacy.","method":"Structural modeling, stable transfection of BAF/3 cells lacking endogenous gp130 with Gly148 or Arg148 variants, IL-6 stimulation proliferation assays, STAT3 phosphorylation assays","journal":"Regulatory peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution in gp130-null cells with mutagenesis and functional readout, single lab","pmids":["17997171"],"is_preprint":false},{"year":2018,"finding":"Quantitative analysis demonstrated that at inflammatory IL-6 concentrations, most IL-6 remains free and uncomplexed with sIL-6R or sgp130, indicating that endogenous sgp130 levels in blood are insufficient to block IL-6 trans-signaling. A single-domain antibody (VHH6) that stabilizes IL-6·sIL-6R complexes drives free IL-6 into complexes and boosts trans-signaling without affecting classic signaling.","method":"Quantitative ELISA measurement of IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, single-domain antibody (VHH6) experiments, functional signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative reconstitution with defined concentrations, orthogonal antibody tool, directly tests the buffer hypothesis experimentally","pmids":["29559558"],"is_preprint":false},{"year":2020,"finding":"Dominant-negative (DN) truncating mutations in IL6ST cause autosomal dominant hyper-IgE syndrome. The mutant GP130 proteins lack the intracellular recycling motif and all four STAT3-recruiting tyrosine residues; they accumulate at the cell surface and are loss-of-function and dominant-negative for cellular responses to IL-6, IL-11, LIF, and OSM. Patient heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11.","method":"Patient genetic analysis, overexpression of mutant alleles, flow cytometry for cell surface accumulation, functional signaling assays in patient leukocytes and fibroblasts, comparison with STAT3-deficient patients","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple patients from 8 kindreds, functional validation with multiple orthogonal methods, mechanistic explanation of dominant-negative mechanism via surface accumulation and loss of recycling motif","pmids":["32207811"],"is_preprint":false},{"year":2020,"finding":"A homozygous variant in IL6ST (p.R281Q) causes selective loss of IL-11 signaling through GP130 without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling, both in vitro in transfected cell lines and patient-derived primary cells, and in vivo in a knock-in mouse model (Il6st p.R279Q) which shows reduced litter size, facial synostosis and teeth abnormalities.","method":"Exome sequencing, transfected cell line signaling assays, primary patient-derived cell assays, CRISPR/Cas9 genome-edited mouse model","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics plus in vitro functional assays plus orthologous mouse model, multiple orthogonal methods demonstrating selective IL-11 signaling defect","pmids":["32566365"],"is_preprint":false},{"year":2021,"finding":"Compound heterozygous missense variants in IL6ST (p.Ala517Pro and p.Gly484_Pro518delinsArg) result in a profound IL-6- and IL-11-dominated signaling defect. Molecular dynamics simulations showed that p.Ala517Pro and p.Asn404Tyr variants increase flexibility of the extracellular membrane-proximal domains of GP130, destabilizing hexameric cytokine receptor complexes while the trimeric LIF-GP130-LIFR complex remains stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site caused additional defective LIF signaling consistent with Stüve-Wiedemann syndrome.","method":"Exome, genome, and RNA sequencing; functional signaling assays for IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF; molecular dynamics simulations; structural modeling of GP130 cytokine receptor complexes","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including structural modeling with MD simulation, functional signaling assays across 8 cytokines, and patient-derived cell validation providing structural basis for cytokine selectivity","pmids":["33771552"],"is_preprint":false},{"year":2021,"finding":"A mosaic gain-of-function IL6ST variant (Tyr186_Tyr190del, present in ~15–40% of cells) causes constitutive IL-6-independent STAT3 hyperphosphorylation at Tyr705 in patient B cell lymphoblastoid cells. This constitutive GP130 activation can be inhibited by the JAK inhibitors ruxolitinib and tofacitinib.","method":"Exome sequencing, western blot for STAT3 phosphorylation in patient EBV-immortalized B cells, JAK inhibitor treatment experiments","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional western blot in patient-derived cells demonstrating constitutive signaling and pharmacological inhibition, single lab","pmids":["33517393"],"is_preprint":false},{"year":2022,"finding":"IL6ST is a substrate of chaperone-mediated autophagy (CMA): it shows KFERQ-dependent binding to the CMA chaperone HSPA8 and accumulates in isolated lysosomes after CMA stimulation by prolonged starvation. Knockdown of the lysosomal CMA receptor LAMP2A increases IL6ST protein levels without changes in mRNA, and promotes cell proliferation and migration in an IL6ST-dependent manner.","method":"LAMP2A knockdown, lysosomal fractionation, HSPA8 co-IP, KFERQ motif mutagenesis (implied), cell proliferation and migration assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (lysosomal fractionation, HSPA8 binding, functional rescue), mechanistically establishes IL6ST as CMA substrate","pmids":["35435804"],"is_preprint":false},{"year":2022,"finding":"GP130/IL6ST is required for TRPA1 upregulation in uninjured (but not injured) sensory neurons after spared nerve injury. Conditional depletion of gp130 in Nav1.8-expressing neurons (SNS-gp130-/- mice) prevented mechanical hypersensitivity after spared nerve injury and reduced Trpa1 mRNA in sensory neurons; adenoviral re-expression of gp130 in vitro partially restored Trpa1 levels.","method":"Conditional knockout mouse model (SNS-gp130-/-), von Frey behavioral testing, ex vivo skin-nerve electrophysiology, RT-PCR for Trpa1 mRNA, adenoviral gp130 re-expression, cinnamaldehyde responsiveness assays","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple readouts (behavioral, electrophysiological, molecular), adenoviral rescue experiment, mechanistically links IL6ST to TRPA1 regulation in nociception","pmids":["34252913"],"is_preprint":false},{"year":2024,"finding":"CryoEM structures of the IL-11 receptor recognition complex (and an IL-11 complex with a disease-associated mutant gp130) reveal how differences in gp130-binding interfaces drive signaling outcomes. Disease-associated IL6ST variants increase flexibility and distance between extracellular domains of GP130; however, distances converge as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signaling consistent with a dimmer switch mode of action.","method":"CryoEM structure determination of IL-11 and IL-6 complexes with wild-type and mutant gp130, molecular dynamics simulations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryoEM structures with MD simulation, direct structural and functional validation of disease variant mechanism","pmids":["38453915"],"is_preprint":false},{"year":2024,"finding":"FXR (farnesoid X receptor) directly binds to the promoters of IL-6ST and IL-6 genes and upregulates their transcription, thereby activating the Jak2/STAT3 signaling pathway to promote tumor migration, invasion, and angiogenesis in non-small cell lung cancer.","method":"Chromatin immunoprecipitation (ChIP) assay demonstrating FXR binding to IL-6ST and IL-6 promoters, in vitro migration/invasion/angiogenesis assays, in vivo mouse metastasis model, natural FXR inhibitor (Z-guggulsterone) experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional assays in vitro and in vivo, single lab","pmids":["38360812"],"is_preprint":false},{"year":2024,"finding":"Cell-autonomous constitutive activation of IL6ST signaling in prostate epithelial cells triggers STAT3 signaling and induces senescence via the STAT3/ARF/p53 axis, recruits cytotoxic T-cells, and suppresses tumor growth in a Pten-deficient prostate cancer mouse model.","method":"Genetic constitutive activation of IL6ST in prostate epithelium in vivo mouse model, transcriptomic analysis, multiplex histopathological analysis, senescence assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic activation with defined molecular pathway (STAT3/ARF/p53) and immune cell readout, single lab","pmids":["39482716"],"is_preprint":false},{"year":2025,"finding":"Truncating IL6ST variants causing dominant-negative hyper-IgE syndrome require premature termination downstream of amino acid F641 (end of transmembrane domain) for LOF and dominant-negative effects. The dominant-negative mechanism operates through accumulation of mutant GP130 on the cell surface due to absence of the recycling motif (positions 782–787). The most upstream truncation linked to HIES was p.K702Sfs7*.","method":"Comprehensive mutagenesis screening of IL6ST truncation variants, flow cytometry for cell surface accumulation, functional signaling assays, patient genetic analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis across the intracellular domain combined with functional assays and surface accumulation measurements defines the structural requirements for dominant-negative activity","pmids":["40526438"],"is_preprint":false},{"year":2025,"finding":"FBXO2 promotes K63-linked ubiquitination of IL6ST, which is required for STAT3 signaling activation during decidualization. Cadmium exposure downregulates FBXO2, reducing IL6ST K63-ubiquitination and suppressing the IL6ST/STAT3 signaling axis, impairing decidualization markers (PRL, IGFBP1, FOXO1).","method":"Co-IP for ubiquitination, FBXO2 overexpression rescue of Cd-induced suppression, in vitro stromal cell models, in vivo Cd-exposed mouse model, western blotting","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating K63-ubiquitination by FBXO2, functional rescue experiments, in vivo validation, single lab","pmids":["41076860"],"is_preprint":false},{"year":2025,"finding":"YEATS2 recruits TAF15 and KAT5 to the promoter region of IL6ST to enhance H3K27ac enrichment, thereby transcriptionally activating IL6ST expression, which promotes NF-κB signaling and malignant progression in esophageal squamous cell carcinoma.","method":"Co-IP-based mass spectrometry, chromatin immunoprecipitation (ChIP) for YEATS2 and H3K27ac at IL6ST promoter, in vitro and in vivo proliferation/migration assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates co-enrichment of YEATS2 and H3K27ac at IL6ST promoter, Co-IP-MS identifies protein partners, functional assays in vitro and in vivo, single lab","pmids":["40040791"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 recognizes and stabilizes m6A-modified IL6ST mRNA, leading to increased IL6ST protein and activation of the JAK2/STAT3 pathway. STAT3, in turn, transcriptionally activates IGF2BP3, forming a positive feedback loop that promotes colorectal cancer progression.","method":"RIP-qPCR demonstrating IGF2BP3 binding to IL6ST mRNA, western blotting, RT-qPCR, animal tumor models, STAT3 transcriptional regulation assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-qPCR demonstrates direct mRNA binding, in vivo animal model, positive feedback loop validated with multiple methods, single lab","pmids":["41286950"],"is_preprint":false},{"year":2006,"finding":"GP130 (CD130) expression on CD4+CD25- T cells correlates with STAT3 phosphorylation upon IL-6 or hyper-IL-6 stimulation, while CD25high regulatory T cells express little CD130 and show reduced STAT3 phosphorylation. GP130 dimerization does not activate MAPK ERK1/2 in these cells, demonstrating selective STAT3 but not MAPK activation by GP130 in T cell subsets.","method":"Flow cytometry for CD126/CD130 expression, phospho-STAT3 and phospho-ERK1/2 intracellular staining, IL-6 and hyper-IL-6 stimulation of human blood, tonsil, and spleen leukocytes","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct flow cytometry measurements in primary human cells with functional signaling readout, replicated across multiple tissue sources, single lab","pmids":["16540526"],"is_preprint":false},{"year":2008,"finding":"LIF signals through LIFR and its co-receptor IL6ST in the ovine uterus. IL6ST mRNA and protein are localized primarily to the middle-to-deep glandular epithelium of the endometrium. Progesterone and interferon tau regulate IL6ST expression in a stage- and cell-specific manner. LIF stimulation of mononuclear trophectoderm and glandular epithelial cells elicits increases in phosphorylated STAT3 and MAPK3/1.","method":"In situ hybridization and immunohistochemistry for LIFR and IL6ST, ovariectomized ewe hormone treatment experiments, LIF stimulation with phospho-STAT3 and phospho-MAPK western blotting","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional signaling readout in primary tissue and cells, hormone regulation demonstrated in vivo, single lab","pmids":["19060097"],"is_preprint":false},{"year":2022,"finding":"IL6ST (gp130) activates the JAK2/STAT3 signaling pathway in cardiomyocytes; knockdown of IL6ST eliminates the mitochondrial ROS scavenging effect and autophagy-promoting effect of silibinin on doxorubicin-injured cardiomyocytes. Molecular docking predicts silibinin binds IL6ST (affinity ≤ -7.0 kcal/mol).","method":"IL6ST siRNA knockdown in AC16 cardiomyocytes, western blot for pathway activation, autophagy assays, ROS measurement, molecular docking","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown phenotype with pathway readout, molecular docking is computational, single lab, no direct binding validation","pmids":["35839932"],"is_preprint":false},{"year":2025,"finding":"Hypomethylation of the IL6ST promoter in endometriosis leads to elevated IL6ST expression and activation of the JAK2/STAT3 pathway in endometrial stromal cells, promoting their viability, invasion, and resistance to apoptosis. JAK2/STAT3 inhibitor WP1066 reversed the proliferative and invasive effects of IL6ST overexpression.","method":"IHC, methylation analysis by bisulfite sequencing, stable transfection of IL6ST overexpression plasmid, CCK-8, Transwell, TUNEL assays, western blot for p-JAK2, p-STAT3, HIF-1α, VEGF","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct methylation analysis linked to functional overexpression phenotype with pathway inhibitor rescue, multiple readouts, single lab","pmids":["39821173"],"is_preprint":false}],"current_model":"IL6ST encodes GP130, a ubiquitously expressed transmembrane signal-transducing receptor subunit that forms the shared β-receptor for at least ten IL-6 family cytokines (IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, CNTF, and others); upon cytokine binding—either through membrane-bound IL-6R (classic signaling) or soluble sIL-6R (trans-signaling)—GP130 undergoes homodimerization or heterodimerization with LIFR/OSMR, activating JAK1/JAK2 kinases that phosphorylate STAT3 at Y705 and also activate MAPK/ERK pathways; gain-of-function in-frame deletions near the transmembrane domain (e.g., Ser187_Tyr190del) cause ligand-independent constitutive STAT3 activation, while truncating or missense mutations in the extracellular membrane-proximal domain (e.g., N404Y, P498L, A517P, R281Q) cause cytokine-selective signaling defects by destabilizing hexameric receptor complexes without disrupting the trimeric LIF-GP130-LIFR complex; dominant-negative truncations that retain the transmembrane domain but lack the intracellular recycling motif (positions 782–787) and STAT3-recruiting tyrosines accumulate at the cell surface and cause autosomal dominant hyper-IgE syndrome; GP130 protein turnover is regulated by chaperone-mediated autophagy via KFERQ-dependent binding to HSPA8 and LAMP2A-mediated lysosomal degradation, and IL6ST mRNA is stabilized by IGF2BP3 recognizing m6A modifications; the soluble extracellular ectodomain (sgp130) acts as a natural decoy receptor that selectively inhibits IL-6 trans-signaling by binding the IL-6·sIL-6R binary complex but not free IL-6, and an alternatively polyadenylated isoform sgp130-E10 shares this selective trans-signaling inhibitory activity."},"narrative":{"mechanistic_narrative":"IL6ST encodes GP130, the shared signal-transducing transmembrane receptor subunit of the IL-6 cytokine family that, upon ligand binding, associates with cytokine-specific receptors to activate JAK2/STAT3 signaling [PMID:1475713, PMID:18650419]. Cytokine engagement assembles GP130 into receptor complexes that drive STAT3 Y705 phosphorylation, with selective coupling to STAT3 over MAPK/ERK in defined cell contexts such as T cell subsets [PMID:16540526], and signaling also achievable through soluble IL-6R (trans-signaling) versus membrane IL-6R (classic signaling) [PMID:21990364]. The membrane-proximal extracellular domains govern cytokine selectivity: structure-guided and molecular-dynamics analyses show that disease variants (N404Y, A517P) increase flexibility of these domains and destabilize hexameric receptor complexes while sparing the trimeric LIF-GP130-LIFR complex, explaining why distinct mutations cause cytokine-selective signaling defects—N404Y abolishes IL-6/IL-11/IL-27/OSM but spares LIF [PMID:28747427], R281Q selectively eliminates IL-11 signaling [PMID:32566365], and combined variants produce IL-6/IL-11-dominated defects [PMID:33771552, PMID:38453915]. The soluble GP130 ectodomain (sgp130), including the alternatively polyadenylated sgp130-E10 isoform, acts as a decoy that selectively inhibits IL-6 trans-signaling by binding the IL-6·sIL-6R complex rather than free IL-6, though endogenous sgp130 levels are insufficient to buffer inflammatory IL-6 concentrations [PMID:21990364, PMID:24973212, PMID:29559558]. IL6ST causes two human Mendelian disorders: gain-of-function in-frame deletions near the transmembrane domain drive ligand-independent constitutive STAT3 activation that is JAK-inhibitor sensitive [PMID:33517393], and dominant-negative truncations downstream of the transmembrane domain that lack the intracellular recycling motif and STAT3-recruiting tyrosines accumulate at the cell surface to cause autosomal dominant hyper-IgE syndrome [PMID:32207811, PMID:40526438]. GP130 abundance is post-transcriptionally controlled by chaperone-mediated autophagy via KFERQ-dependent HSPA8 binding and LAMP2A-mediated lysosomal degradation [PMID:35435804], by K63-linked ubiquitination through FBXO2 that is required for STAT3 activation during decidualization [PMID:41076860], and by IGF2BP3-mediated stabilization of m6A-modified IL6ST mRNA [PMID:41286950], while transcription is driven by FXR, YEATS2-recruited chromatin modifiers, and promoter methylation status in various cancers [PMID:38360812, PMID:40040791, PMID:39821173]. Through the GP130/JAK2/STAT3 axis IL6ST contributes to nociceptor TRPA1 regulation [PMID:34252913], context-dependent tumor promotion or senescence-mediated suppression [PMID:39482716, PMID:41286950], and reproductive endometrial signaling [PMID:19060097].","teleology":[{"year":1992,"claim":"Established the foundational identity of GP130 as the signal-transducing component of the IL-6 receptor complex, distinguishing the receptor's ligand-binding from its signaling function.","evidence":"Gene characterization and functional receptor association assays","pmids":["1475713"],"confidence":"Medium","gaps":["Did not resolve downstream kinase coupling","No structural basis for receptor assembly"]},{"year":2007,"claim":"Showed that single extracellular residues tune GP130 signaling efficacy, establishing that natural variation modulates STAT3 output.","evidence":"Reconstitution of Gly148/Arg148 variants in gp130-null BAF/3 cells with proliferation and pSTAT3 readouts","pmids":["17997171"],"confidence":"Medium","gaps":["Single polymorphism, no disease link","Mechanism of affinity change not structurally resolved"]},{"year":2008,"claim":"Defined the structural determinants of GP130's interaction with the IL-6/sIL-6R complex and engineered selective trans-signaling inhibition, separating classic from trans-signaling at the receptor level.","evidence":"3D structural analysis, NMR of membrane-proximal domain, site-directed mutagenesis, in vitro and mouse inflammation assays","pmids":["18650419"],"confidence":"High","gaps":["Species-specific interactions complicate translation","Did not map all selectivity-determining residues"]},{"year":2011,"claim":"Resolved the selectivity and concentration-dependence of sgp130 inhibition and identified the colon as a tissue dominated by IL-6 trans-signaling.","evidence":"Quantitative binding studies, proliferation inhibition, tocilizumab comparison, in vivo sgp130Fc mouse experiments","pmids":["21990364"],"confidence":"High","gaps":["Endogenous sgp130 sufficiency not yet quantified","Tissue selectivity mechanism unclear"]},{"year":2014,"claim":"Identified a novel alternatively polyadenylated soluble isoform sgp130-E10 with selective trans-signaling inhibitory activity, expanding the natural decoy repertoire.","evidence":"Molecular cloning, PBMC expression, Fc-fusion binding and trans-signaling inhibition assays","pmids":["24973212"],"confidence":"High","gaps":["Physiological abundance and regulation of sgp130-E10 unknown","In vivo role not tested"]},{"year":2006,"claim":"Demonstrated cell-type-selective signaling output, with GP130 driving STAT3 but not MAPK/ERK in T cell subsets and minimal expression on regulatory T cells.","evidence":"Flow cytometry and phospho-STAT3/ERK staining in primary human leukocytes","pmids":["16540526"],"confidence":"Medium","gaps":["Basis for selective pathway coupling unresolved","Correlative, not causal for Treg biology"]},{"year":2017,"claim":"First demonstrated cytokine-selective human loss-of-function (N404Y), proving a single GP130 residue is differentially required across the cytokine family.","evidence":"Patient genetics and functional signaling assays in patient-derived cells across multiple cytokines","pmids":["28747427"],"confidence":"High","gaps":["Structural basis of selectivity not yet defined at this stage","Single-residue, single-family generalization untested"]},{"year":2020,"claim":"Defined the dominant-negative mechanism of autosomal dominant hyper-IgE syndrome, showing mutant GP130 lacking the recycling motif and STAT3 tyrosines accumulates at the surface and broadly blocks IL-6 family signaling.","evidence":"Patient genetics across 8 kindreds, mutant overexpression, surface-accumulation flow cytometry, signaling assays in patient cells","pmids":["32207811"],"confidence":"High","gaps":["Precise structural requirements of truncation not yet mapped","How surface accumulation suppresses WT signaling not fully resolved"]},{"year":2020,"claim":"Established IL-11-selective loss of function (R281Q) with an orthologous mouse model, linking GP130 cytokine selectivity to skeletal/craniofacial phenotypes.","evidence":"Exome sequencing, transfected and primary cell signaling assays, CRISPR knock-in mouse","pmids":["32566365"],"confidence":"High","gaps":["Structural basis for IL-11 selectivity not yet shown","Tissue specificity of the defect not fully explained"]},{"year":2021,"claim":"Provided the structural mechanism for cytokine selectivity, showing disease variants destabilize hexameric complexes while sparing the trimeric LIF-GP130-LIFR complex via a distinct membrane-proximal interaction.","evidence":"Multi-omic patient sequencing, eight-cytokine signaling assays, molecular dynamics and structural modeling","pmids":["33771552"],"confidence":"High","gaps":["Direct structural confirmation by experimental structure pending at this stage","Compound heterozygote rarity limits generalization"]},{"year":2021,"claim":"Identified mosaic gain-of-function in-frame deletion causing ligand-independent constitutive STAT3 hyperactivation that is pharmacologically reversible with JAK inhibitors.","evidence":"Exome sequencing, pSTAT3 western blot in patient B cells, ruxolitinib/tofacitinib treatment","pmids":["33517393"],"confidence":"Medium","gaps":["Single patient/lab","Structural basis of constitutive activation not resolved here"]},{"year":2018,"claim":"Tested the sgp130 buffer hypothesis quantitatively, showing endogenous sgp130 is insufficient to block inflammatory trans-signaling, and that an antibody stabilizing IL-6·sIL-6R can selectively boost trans-signaling.","evidence":"Quantitative ELISA of complexes, single-domain antibody VHH6, functional signaling assays","pmids":["29559558"],"confidence":"High","gaps":["In vivo buffering during disease not measured","Generalizability across tissues unknown"]},{"year":2022,"claim":"Established GP130 protein abundance as autophagy-regulated, identifying it as a KFERQ/HSPA8/LAMP2A chaperone-mediated autophagy substrate that controls proliferation and migration.","evidence":"LAMP2A knockdown, lysosomal fractionation, HSPA8 co-IP, functional rescue assays","pmids":["35435804"],"confidence":"High","gaps":["KFERQ motif location not explicitly mapped","Physiological trigger of GP130 CMA in vivo unknown"]},{"year":2022,"claim":"Linked GP130 to nociception by showing it is required for TRPA1 upregulation in uninjured sensory neurons and for mechanical hypersensitivity after nerve injury.","evidence":"Conditional SNS-gp130 knockout, behavioral, electrophysiological and RT-PCR readouts, adenoviral rescue","pmids":["34252913"],"confidence":"High","gaps":["Cytokine driving the neuronal effect not identified","Direct GP130-to-Trpa1 transcriptional link not resolved"]},{"year":2024,"claim":"Provided cryoEM structures of IL-11 and IL-6 receptor recognition complexes with wild-type and mutant GP130, supporting a 'dimmer switch' model where geometric stringency at the membrane controls signaling.","evidence":"CryoEM structure determination and molecular dynamics simulations","pmids":["38453915"],"confidence":"High","gaps":["Full transmembrane/intracellular signaling geometry not resolved","Dynamics of signaling activation not directly visualized"]},{"year":2024,"claim":"Showed transcriptional control of IL6ST by FXR, coupling nuclear receptor activity to JAK2/STAT3-driven tumor migration and angiogenesis in lung cancer.","evidence":"ChIP, in vitro migration/invasion/angiogenesis assays, in vivo metastasis model, FXR inhibitor","pmids":["38360812"],"confidence":"Medium","gaps":["Single lab","Relative contribution of IL6ST vs IL-6 promoter binding not dissected"]},{"year":2024,"claim":"Demonstrated context-dependent tumor suppression, where constitutive IL6ST/STAT3 activation in prostate epithelium induces senescence via STAT3/ARF/p53 and recruits cytotoxic T cells.","evidence":"Genetic constitutive IL6ST activation in mouse prostate, transcriptomics, histopathology, senescence assays","pmids":["39482716"],"confidence":"Medium","gaps":["Single model/lab","Determinants of pro- vs anti-tumor outcome unresolved"]},{"year":2025,"claim":"Systematically defined the truncation boundaries required for dominant-negative hyper-IgE syndrome, pinpointing loss of the intracellular recycling motif (782-787) and surface accumulation as the mechanism.","evidence":"Comprehensive truncation mutagenesis, surface-accumulation flow cytometry, signaling assays, patient genetics","pmids":["40526438"],"confidence":"High","gaps":["Mechanism by which surface-retained mutant suppresses WT GP130 not fully resolved"]},{"year":2025,"claim":"Identified FBXO2-mediated K63 ubiquitination as a post-translational requirement for IL6ST/STAT3 activation during decidualization and a target of cadmium toxicity.","evidence":"Co-IP ubiquitination, FBXO2 overexpression rescue, in vitro stromal models, in vivo cadmium mouse model","pmids":["41076860"],"confidence":"Medium","gaps":["Ubiquitination site on IL6ST not mapped","Single lab"]},{"year":2025,"claim":"Showed chromatin and RNA-level regulation of IL6ST, including YEATS2/TAF15/KAT5-driven H3K27ac promoter activation and IGF2BP3-mediated m6A mRNA stabilization in a STAT3 feedback loop.","evidence":"Co-IP-MS, ChIP, RIP-qPCR, in vitro and in vivo tumor assays","pmids":["40040791","41286950"],"confidence":"Medium","gaps":["Single-lab cancer-specific findings","Generalizability of feedback loop beyond these tumors untested"]},{"year":null,"claim":"How the diverse post-transcriptional, ubiquitination, and chaperone-mediated autophagy controls of GP130 abundance are integrated with cytokine-specific receptor geometry to set context-dependent STAT3 output in physiology versus disease remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking abundance regulation to 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Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity) Binds to the soluble IL6:sIL6R complex (hyper-IL6), thereby blocking IL6 trans-signaling. Inhibits sIL6R-dependent acute phase response (PubMed:11121117, PubMed:21990364, PubMed:30279168). 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STWS2","url":"https://www.omim.org/entry/619751"},{"mim_id":"619750","title":"IMMUNODEFICIENCY 94 WITH AUTOINFLAMMATION AND DYSMORPHIC FACIES; IMD94","url":"https://www.omim.org/entry/619750"},{"mim_id":"618523","title":"HYPER-IgE SYNDROME 4B, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS; HIES4B","url":"https://www.omim.org/entry/618523"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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assays\",\n      \"journal\": \"Somatic cell and molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — foundational characterization with functional receptor association, replicated across multiple subsequent studies confirming signal transduction role\",\n      \"pmids\": [\"1475713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The active IL6ST gene is located at chromosome band 5q11; a nontranscribed pseudogene exists at chromosome band 17p11.\",\n      \"method\": \"Chromosomal localization by fluorescence in situ hybridization and somatic cell genetics\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping experiment, single lab but clear result distinguishing active gene from pseudogene\",\n      \"pmids\": [\"7736792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Structure-guided mutagenesis of gp130 identified amino acid residues in the extracellular domain (particularly in the cytokine-binding domain) that, when mutated, increase binding affinity to the IL-6/sIL-6R complex. A triple mutein (T102Y/Q113F/N114L) showed additive improvement in binding affinity and selective inhibition of IL-6 trans-signaling without affecting classic signaling, demonstrating species specificity of these interactions.\",\n      \"method\": \"3D structural analysis of gp130 in complex with IL-6 and sIL-6R, NMR analysis of membrane-proximal domain, site-directed mutagenesis, in vitro cell proliferation assays, acute phase gene expression assays, mouse model of acute inflammation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided mutagenesis combined with in vitro functional assays and in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18650419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling via sIL-6R but, under conditions of molar excess of sIL-6R over IL-6, can also trap free IL-6 into IL-6·sIL-6R·sgp130 ternary complexes, thereby inhibiting classic signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, identifying the colon as a prominent target of IL-6 trans-signaling.\",\n      \"method\": \"Quantitative binding studies, cell proliferation inhibition assays, comparison with anti-IL-6R antibody tocilizumab, in vivo mouse experiments with sgp130Fc\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of signaling complexes, in vivo validation, multiple orthogonal methods, mechanistically defines the selectivity of sgp130 inhibition\",\n      \"pmids\": [\"21990364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Alternative intronic polyadenylation in intron 10 of the gp130 (IL6ST) transcript generates a novel soluble isoform, sgp130-E10 (70–80 kDa). The sgp130-E10 protein binds to the IL-6/sIL-6R complex but not to IL-6 alone, and specifically inhibits IL-6 trans-signaling.\",\n      \"method\": \"Molecular cloning, expression in human PBMCs, recombinant protein production as Fc-fusion, binding assays, IL-6 trans-signaling inhibition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic identification of novel isoform with functional validation using binding and signaling assays, in vitro reconstitution\",\n      \"pmids\": [\"24973212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous missense mutation in IL6ST (p.N404Y) causes loss of IL-6, IL-11, IL-27, and OSM signaling through GP130 while largely preserving LIF signaling, demonstrating that the N404 residue is selectively required for a subset of GP130 cytokine responses.\",\n      \"method\": \"Patient genetic analysis, functional signaling assays in patient-derived cells, cytokine stimulation experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function variant in human patient with functional validation across multiple cytokines, replicated in subsequent studies\",\n      \"pmids\": [\"28747427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A non-conservative polymorphism in gp130 (Gly148Arg) reduces cellular proliferation and STAT3 phosphorylation in response to gp130 stimulation, demonstrating that this residue influences GP130 signaling efficacy.\",\n      \"method\": \"Structural modeling, stable transfection of BAF/3 cells lacking endogenous gp130 with Gly148 or Arg148 variants, IL-6 stimulation proliferation assays, STAT3 phosphorylation assays\",\n      \"journal\": \"Regulatory peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution in gp130-null cells with mutagenesis and functional readout, single lab\",\n      \"pmids\": [\"17997171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Quantitative analysis demonstrated that at inflammatory IL-6 concentrations, most IL-6 remains free and uncomplexed with sIL-6R or sgp130, indicating that endogenous sgp130 levels in blood are insufficient to block IL-6 trans-signaling. A single-domain antibody (VHH6) that stabilizes IL-6·sIL-6R complexes drives free IL-6 into complexes and boosts trans-signaling without affecting classic signaling.\",\n      \"method\": \"Quantitative ELISA measurement of IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, single-domain antibody (VHH6) experiments, functional signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative reconstitution with defined concentrations, orthogonal antibody tool, directly tests the buffer hypothesis experimentally\",\n      \"pmids\": [\"29559558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dominant-negative (DN) truncating mutations in IL6ST cause autosomal dominant hyper-IgE syndrome. The mutant GP130 proteins lack the intracellular recycling motif and all four STAT3-recruiting tyrosine residues; they accumulate at the cell surface and are loss-of-function and dominant-negative for cellular responses to IL-6, IL-11, LIF, and OSM. Patient heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11.\",\n      \"method\": \"Patient genetic analysis, overexpression of mutant alleles, flow cytometry for cell surface accumulation, functional signaling assays in patient leukocytes and fibroblasts, comparison with STAT3-deficient patients\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple patients from 8 kindreds, functional validation with multiple orthogonal methods, mechanistic explanation of dominant-negative mechanism via surface accumulation and loss of recycling motif\",\n      \"pmids\": [\"32207811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A homozygous variant in IL6ST (p.R281Q) causes selective loss of IL-11 signaling through GP130 without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling, both in vitro in transfected cell lines and patient-derived primary cells, and in vivo in a knock-in mouse model (Il6st p.R279Q) which shows reduced litter size, facial synostosis and teeth abnormalities.\",\n      \"method\": \"Exome sequencing, transfected cell line signaling assays, primary patient-derived cell assays, CRISPR/Cas9 genome-edited mouse model\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics plus in vitro functional assays plus orthologous mouse model, multiple orthogonal methods demonstrating selective IL-11 signaling defect\",\n      \"pmids\": [\"32566365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound heterozygous missense variants in IL6ST (p.Ala517Pro and p.Gly484_Pro518delinsArg) result in a profound IL-6- and IL-11-dominated signaling defect. Molecular dynamics simulations showed that p.Ala517Pro and p.Asn404Tyr variants increase flexibility of the extracellular membrane-proximal domains of GP130, destabilizing hexameric cytokine receptor complexes while the trimeric LIF-GP130-LIFR complex remains stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site caused additional defective LIF signaling consistent with Stüve-Wiedemann syndrome.\",\n      \"method\": \"Exome, genome, and RNA sequencing; functional signaling assays for IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF; molecular dynamics simulations; structural modeling of GP130 cytokine receptor complexes\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including structural modeling with MD simulation, functional signaling assays across 8 cytokines, and patient-derived cell validation providing structural basis for cytokine selectivity\",\n      \"pmids\": [\"33771552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A mosaic gain-of-function IL6ST variant (Tyr186_Tyr190del, present in ~15–40% of cells) causes constitutive IL-6-independent STAT3 hyperphosphorylation at Tyr705 in patient B cell lymphoblastoid cells. This constitutive GP130 activation can be inhibited by the JAK inhibitors ruxolitinib and tofacitinib.\",\n      \"method\": \"Exome sequencing, western blot for STAT3 phosphorylation in patient EBV-immortalized B cells, JAK inhibitor treatment experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional western blot in patient-derived cells demonstrating constitutive signaling and pharmacological inhibition, single lab\",\n      \"pmids\": [\"33517393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL6ST is a substrate of chaperone-mediated autophagy (CMA): it shows KFERQ-dependent binding to the CMA chaperone HSPA8 and accumulates in isolated lysosomes after CMA stimulation by prolonged starvation. Knockdown of the lysosomal CMA receptor LAMP2A increases IL6ST protein levels without changes in mRNA, and promotes cell proliferation and migration in an IL6ST-dependent manner.\",\n      \"method\": \"LAMP2A knockdown, lysosomal fractionation, HSPA8 co-IP, KFERQ motif mutagenesis (implied), cell proliferation and migration assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (lysosomal fractionation, HSPA8 binding, functional rescue), mechanistically establishes IL6ST as CMA substrate\",\n      \"pmids\": [\"35435804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GP130/IL6ST is required for TRPA1 upregulation in uninjured (but not injured) sensory neurons after spared nerve injury. Conditional depletion of gp130 in Nav1.8-expressing neurons (SNS-gp130-/- mice) prevented mechanical hypersensitivity after spared nerve injury and reduced Trpa1 mRNA in sensory neurons; adenoviral re-expression of gp130 in vitro partially restored Trpa1 levels.\",\n      \"method\": \"Conditional knockout mouse model (SNS-gp130-/-), von Frey behavioral testing, ex vivo skin-nerve electrophysiology, RT-PCR for Trpa1 mRNA, adenoviral gp130 re-expression, cinnamaldehyde responsiveness assays\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple readouts (behavioral, electrophysiological, molecular), adenoviral rescue experiment, mechanistically links IL6ST to TRPA1 regulation in nociception\",\n      \"pmids\": [\"34252913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CryoEM structures of the IL-11 receptor recognition complex (and an IL-11 complex with a disease-associated mutant gp130) reveal how differences in gp130-binding interfaces drive signaling outcomes. Disease-associated IL6ST variants increase flexibility and distance between extracellular domains of GP130; however, distances converge as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signaling consistent with a dimmer switch mode of action.\",\n      \"method\": \"CryoEM structure determination of IL-11 and IL-6 complexes with wild-type and mutant gp130, molecular dynamics simulations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryoEM structures with MD simulation, direct structural and functional validation of disease variant mechanism\",\n      \"pmids\": [\"38453915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FXR (farnesoid X receptor) directly binds to the promoters of IL-6ST and IL-6 genes and upregulates their transcription, thereby activating the Jak2/STAT3 signaling pathway to promote tumor migration, invasion, and angiogenesis in non-small cell lung cancer.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay demonstrating FXR binding to IL-6ST and IL-6 promoters, in vitro migration/invasion/angiogenesis assays, in vivo mouse metastasis model, natural FXR inhibitor (Z-guggulsterone) experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"38360812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cell-autonomous constitutive activation of IL6ST signaling in prostate epithelial cells triggers STAT3 signaling and induces senescence via the STAT3/ARF/p53 axis, recruits cytotoxic T-cells, and suppresses tumor growth in a Pten-deficient prostate cancer mouse model.\",\n      \"method\": \"Genetic constitutive activation of IL6ST in prostate epithelium in vivo mouse model, transcriptomic analysis, multiplex histopathological analysis, senescence assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic activation with defined molecular pathway (STAT3/ARF/p53) and immune cell readout, single lab\",\n      \"pmids\": [\"39482716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Truncating IL6ST variants causing dominant-negative hyper-IgE syndrome require premature termination downstream of amino acid F641 (end of transmembrane domain) for LOF and dominant-negative effects. The dominant-negative mechanism operates through accumulation of mutant GP130 on the cell surface due to absence of the recycling motif (positions 782–787). The most upstream truncation linked to HIES was p.K702Sfs7*.\",\n      \"method\": \"Comprehensive mutagenesis screening of IL6ST truncation variants, flow cytometry for cell surface accumulation, functional signaling assays, patient genetic analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis across the intracellular domain combined with functional assays and surface accumulation measurements defines the structural requirements for dominant-negative activity\",\n      \"pmids\": [\"40526438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 promotes K63-linked ubiquitination of IL6ST, which is required for STAT3 signaling activation during decidualization. Cadmium exposure downregulates FBXO2, reducing IL6ST K63-ubiquitination and suppressing the IL6ST/STAT3 signaling axis, impairing decidualization markers (PRL, IGFBP1, FOXO1).\",\n      \"method\": \"Co-IP for ubiquitination, FBXO2 overexpression rescue of Cd-induced suppression, in vitro stromal cell models, in vivo Cd-exposed mouse model, western blotting\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating K63-ubiquitination by FBXO2, functional rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"41076860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 recruits TAF15 and KAT5 to the promoter region of IL6ST to enhance H3K27ac enrichment, thereby transcriptionally activating IL6ST expression, which promotes NF-κB signaling and malignant progression in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-IP-based mass spectrometry, chromatin immunoprecipitation (ChIP) for YEATS2 and H3K27ac at IL6ST promoter, in vitro and in vivo proliferation/migration assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates co-enrichment of YEATS2 and H3K27ac at IL6ST promoter, Co-IP-MS identifies protein partners, functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"40040791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 recognizes and stabilizes m6A-modified IL6ST mRNA, leading to increased IL6ST protein and activation of the JAK2/STAT3 pathway. STAT3, in turn, transcriptionally activates IGF2BP3, forming a positive feedback loop that promotes colorectal cancer progression.\",\n      \"method\": \"RIP-qPCR demonstrating IGF2BP3 binding to IL6ST mRNA, western blotting, RT-qPCR, animal tumor models, STAT3 transcriptional regulation assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-qPCR demonstrates direct mRNA binding, in vivo animal model, positive feedback loop validated with multiple methods, single lab\",\n      \"pmids\": [\"41286950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GP130 (CD130) expression on CD4+CD25- T cells correlates with STAT3 phosphorylation upon IL-6 or hyper-IL-6 stimulation, while CD25high regulatory T cells express little CD130 and show reduced STAT3 phosphorylation. GP130 dimerization does not activate MAPK ERK1/2 in these cells, demonstrating selective STAT3 but not MAPK activation by GP130 in T cell subsets.\",\n      \"method\": \"Flow cytometry for CD126/CD130 expression, phospho-STAT3 and phospho-ERK1/2 intracellular staining, IL-6 and hyper-IL-6 stimulation of human blood, tonsil, and spleen leukocytes\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct flow cytometry measurements in primary human cells with functional signaling readout, replicated across multiple tissue sources, single lab\",\n      \"pmids\": [\"16540526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LIF signals through LIFR and its co-receptor IL6ST in the ovine uterus. IL6ST mRNA and protein are localized primarily to the middle-to-deep glandular epithelium of the endometrium. Progesterone and interferon tau regulate IL6ST expression in a stage- and cell-specific manner. LIF stimulation of mononuclear trophectoderm and glandular epithelial cells elicits increases in phosphorylated STAT3 and MAPK3/1.\",\n      \"method\": \"In situ hybridization and immunohistochemistry for LIFR and IL6ST, ovariectomized ewe hormone treatment experiments, LIF stimulation with phospho-STAT3 and phospho-MAPK western blotting\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional signaling readout in primary tissue and cells, hormone regulation demonstrated in vivo, single lab\",\n      \"pmids\": [\"19060097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL6ST (gp130) activates the JAK2/STAT3 signaling pathway in cardiomyocytes; knockdown of IL6ST eliminates the mitochondrial ROS scavenging effect and autophagy-promoting effect of silibinin on doxorubicin-injured cardiomyocytes. Molecular docking predicts silibinin binds IL6ST (affinity ≤ -7.0 kcal/mol).\",\n      \"method\": \"IL6ST siRNA knockdown in AC16 cardiomyocytes, western blot for pathway activation, autophagy assays, ROS measurement, molecular docking\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown phenotype with pathway readout, molecular docking is computational, single lab, no direct binding validation\",\n      \"pmids\": [\"35839932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypomethylation of the IL6ST promoter in endometriosis leads to elevated IL6ST expression and activation of the JAK2/STAT3 pathway in endometrial stromal cells, promoting their viability, invasion, and resistance to apoptosis. JAK2/STAT3 inhibitor WP1066 reversed the proliferative and invasive effects of IL6ST overexpression.\",\n      \"method\": \"IHC, methylation analysis by bisulfite sequencing, stable transfection of IL6ST overexpression plasmid, CCK-8, Transwell, TUNEL assays, western blot for p-JAK2, p-STAT3, HIF-1α, VEGF\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct methylation analysis linked to functional overexpression phenotype with pathway inhibitor rescue, multiple readouts, single lab\",\n      \"pmids\": [\"39821173\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL6ST encodes GP130, a ubiquitously expressed transmembrane signal-transducing receptor subunit that forms the shared β-receptor for at least ten IL-6 family cytokines (IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, CNTF, and others); upon cytokine binding—either through membrane-bound IL-6R (classic signaling) or soluble sIL-6R (trans-signaling)—GP130 undergoes homodimerization or heterodimerization with LIFR/OSMR, activating JAK1/JAK2 kinases that phosphorylate STAT3 at Y705 and also activate MAPK/ERK pathways; gain-of-function in-frame deletions near the transmembrane domain (e.g., Ser187_Tyr190del) cause ligand-independent constitutive STAT3 activation, while truncating or missense mutations in the extracellular membrane-proximal domain (e.g., N404Y, P498L, A517P, R281Q) cause cytokine-selective signaling defects by destabilizing hexameric receptor complexes without disrupting the trimeric LIF-GP130-LIFR complex; dominant-negative truncations that retain the transmembrane domain but lack the intracellular recycling motif (positions 782–787) and STAT3-recruiting tyrosines accumulate at the cell surface and cause autosomal dominant hyper-IgE syndrome; GP130 protein turnover is regulated by chaperone-mediated autophagy via KFERQ-dependent binding to HSPA8 and LAMP2A-mediated lysosomal degradation, and IL6ST mRNA is stabilized by IGF2BP3 recognizing m6A modifications; the soluble extracellular ectodomain (sgp130) acts as a natural decoy receptor that selectively inhibits IL-6 trans-signaling by binding the IL-6·sIL-6R binary complex but not free IL-6, and an alternatively polyadenylated isoform sgp130-E10 shares this selective trans-signaling inhibitory activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL6ST encodes GP130, the shared signal-transducing transmembrane receptor subunit of the IL-6 cytokine family that, upon ligand binding, associates with cytokine-specific receptors to activate JAK2/STAT3 signaling [#0, #2]. Cytokine engagement assembles GP130 into receptor complexes that drive STAT3 Y705 phosphorylation, with selective coupling to STAT3 over MAPK/ERK in defined cell contexts such as T cell subsets [#21], and signaling also achievable through soluble IL-6R (trans-signaling) versus membrane IL-6R (classic signaling) [#3]. The membrane-proximal extracellular domains govern cytokine selectivity: structure-guided and molecular-dynamics analyses show that disease variants (N404Y, A517P) increase flexibility of these domains and destabilize hexameric receptor complexes while sparing the trimeric LIF-GP130-LIFR complex, explaining why distinct mutations cause cytokine-selective signaling defects—N404Y abolishes IL-6/IL-11/IL-27/OSM but spares LIF [#5], R281Q selectively eliminates IL-11 signaling [#9], and combined variants produce IL-6/IL-11-dominated defects [#10, #14]. The soluble GP130 ectodomain (sgp130), including the alternatively polyadenylated sgp130-E10 isoform, acts as a decoy that selectively inhibits IL-6 trans-signaling by binding the IL-6·sIL-6R complex rather than free IL-6, though endogenous sgp130 levels are insufficient to buffer inflammatory IL-6 concentrations [#3, #4, #7]. IL6ST causes two human Mendelian disorders: gain-of-function in-frame deletions near the transmembrane domain drive ligand-independent constitutive STAT3 activation that is JAK-inhibitor sensitive [#11], and dominant-negative truncations downstream of the transmembrane domain that lack the intracellular recycling motif and STAT3-recruiting tyrosines accumulate at the cell surface to cause autosomal dominant hyper-IgE syndrome [#8, #17]. GP130 abundance is post-transcriptionally controlled by chaperone-mediated autophagy via KFERQ-dependent HSPA8 binding and LAMP2A-mediated lysosomal degradation [#12], by K63-linked ubiquitination through FBXO2 that is required for STAT3 activation during decidualization [#18], and by IGF2BP3-mediated stabilization of m6A-modified IL6ST mRNA [#20], while transcription is driven by FXR, YEATS2-recruited chromatin modifiers, and promoter methylation status in various cancers [#15, #19, #24]. Through the GP130/JAK2/STAT3 axis IL6ST contributes to nociceptor TRPA1 regulation [#13], context-dependent tumor promotion or senescence-mediated suppression [#16, #20], and reproductive endometrial signaling [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the foundational identity of GP130 as the signal-transducing component of the IL-6 receptor complex, distinguishing the receptor's ligand-binding from its signaling function.\",\n      \"evidence\": \"Gene characterization and functional receptor association assays\",\n      \"pmids\": [\"1475713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve downstream kinase coupling\", \"No structural basis for receptor assembly\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that single extracellular residues tune GP130 signaling efficacy, establishing that natural variation modulates STAT3 output.\",\n      \"evidence\": \"Reconstitution of Gly148/Arg148 variants in gp130-null BAF/3 cells with proliferation and pSTAT3 readouts\",\n      \"pmids\": [\"17997171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single polymorphism, no disease link\", \"Mechanism of affinity change not structurally resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the structural determinants of GP130's interaction with the IL-6/sIL-6R complex and engineered selective trans-signaling inhibition, separating classic from trans-signaling at the receptor level.\",\n      \"evidence\": \"3D structural analysis, NMR of membrane-proximal domain, site-directed mutagenesis, in vitro and mouse inflammation assays\",\n      \"pmids\": [\"18650419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species-specific interactions complicate translation\", \"Did not map all selectivity-determining residues\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the selectivity and concentration-dependence of sgp130 inhibition and identified the colon as a tissue dominated by IL-6 trans-signaling.\",\n      \"evidence\": \"Quantitative binding studies, proliferation inhibition, tocilizumab comparison, in vivo sgp130Fc mouse experiments\",\n      \"pmids\": [\"21990364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous sgp130 sufficiency not yet quantified\", \"Tissue selectivity mechanism unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a novel alternatively polyadenylated soluble isoform sgp130-E10 with selective trans-signaling inhibitory activity, expanding the natural decoy repertoire.\",\n      \"evidence\": \"Molecular cloning, PBMC expression, Fc-fusion binding and trans-signaling inhibition assays\",\n      \"pmids\": [\"24973212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological abundance and regulation of sgp130-E10 unknown\", \"In vivo role not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated cell-type-selective signaling output, with GP130 driving STAT3 but not MAPK/ERK in T cell subsets and minimal expression on regulatory T cells.\",\n      \"evidence\": \"Flow cytometry and phospho-STAT3/ERK staining in primary human leukocytes\",\n      \"pmids\": [\"16540526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for selective pathway coupling unresolved\", \"Correlative, not causal for Treg biology\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"First demonstrated cytokine-selective human loss-of-function (N404Y), proving a single GP130 residue is differentially required across the cytokine family.\",\n      \"evidence\": \"Patient genetics and functional signaling assays in patient-derived cells across multiple cytokines\",\n      \"pmids\": [\"28747427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of selectivity not yet defined at this stage\", \"Single-residue, single-family generalization untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the dominant-negative mechanism of autosomal dominant hyper-IgE syndrome, showing mutant GP130 lacking the recycling motif and STAT3 tyrosines accumulates at the surface and broadly blocks IL-6 family signaling.\",\n      \"evidence\": \"Patient genetics across 8 kindreds, mutant overexpression, surface-accumulation flow cytometry, signaling assays in patient cells\",\n      \"pmids\": [\"32207811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural requirements of truncation not yet mapped\", \"How surface accumulation suppresses WT signaling not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established IL-11-selective loss of function (R281Q) with an orthologous mouse model, linking GP130 cytokine selectivity to skeletal/craniofacial phenotypes.\",\n      \"evidence\": \"Exome sequencing, transfected and primary cell signaling assays, CRISPR knock-in mouse\",\n      \"pmids\": [\"32566365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for IL-11 selectivity not yet shown\", \"Tissue specificity of the defect not fully explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural mechanism for cytokine selectivity, showing disease variants destabilize hexameric complexes while sparing the trimeric LIF-GP130-LIFR complex via a distinct membrane-proximal interaction.\",\n      \"evidence\": \"Multi-omic patient sequencing, eight-cytokine signaling assays, molecular dynamics and structural modeling\",\n      \"pmids\": [\"33771552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural confirmation by experimental structure pending at this stage\", \"Compound heterozygote rarity limits generalization\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified mosaic gain-of-function in-frame deletion causing ligand-independent constitutive STAT3 hyperactivation that is pharmacologically reversible with JAK inhibitors.\",\n      \"evidence\": \"Exome sequencing, pSTAT3 western blot in patient B cells, ruxolitinib/tofacitinib treatment\",\n      \"pmids\": [\"33517393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient/lab\", \"Structural basis of constitutive activation not resolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tested the sgp130 buffer hypothesis quantitatively, showing endogenous sgp130 is insufficient to block inflammatory trans-signaling, and that an antibody stabilizing IL-6·sIL-6R can selectively boost trans-signaling.\",\n      \"evidence\": \"Quantitative ELISA of complexes, single-domain antibody VHH6, functional signaling assays\",\n      \"pmids\": [\"29559558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo buffering during disease not measured\", \"Generalizability across tissues unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established GP130 protein abundance as autophagy-regulated, identifying it as a KFERQ/HSPA8/LAMP2A chaperone-mediated autophagy substrate that controls proliferation and migration.\",\n      \"evidence\": \"LAMP2A knockdown, lysosomal fractionation, HSPA8 co-IP, functional rescue assays\",\n      \"pmids\": [\"35435804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KFERQ motif location not explicitly mapped\", \"Physiological trigger of GP130 CMA in vivo unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked GP130 to nociception by showing it is required for TRPA1 upregulation in uninjured sensory neurons and for mechanical hypersensitivity after nerve injury.\",\n      \"evidence\": \"Conditional SNS-gp130 knockout, behavioral, electrophysiological and RT-PCR readouts, adenoviral rescue\",\n      \"pmids\": [\"34252913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytokine driving the neuronal effect not identified\", \"Direct GP130-to-Trpa1 transcriptional link not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided cryoEM structures of IL-11 and IL-6 receptor recognition complexes with wild-type and mutant GP130, supporting a 'dimmer switch' model where geometric stringency at the membrane controls signaling.\",\n      \"evidence\": \"CryoEM structure determination and molecular dynamics simulations\",\n      \"pmids\": [\"38453915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full transmembrane/intracellular signaling geometry not resolved\", \"Dynamics of signaling activation not directly visualized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed transcriptional control of IL6ST by FXR, coupling nuclear receptor activity to JAK2/STAT3-driven tumor migration and angiogenesis in lung cancer.\",\n      \"evidence\": \"ChIP, in vitro migration/invasion/angiogenesis assays, in vivo metastasis model, FXR inhibitor\",\n      \"pmids\": [\"38360812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution of IL6ST vs IL-6 promoter binding not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated context-dependent tumor suppression, where constitutive IL6ST/STAT3 activation in prostate epithelium induces senescence via STAT3/ARF/p53 and recruits cytotoxic T cells.\",\n      \"evidence\": \"Genetic constitutive IL6ST activation in mouse prostate, transcriptomics, histopathology, senescence assays\",\n      \"pmids\": [\"39482716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single model/lab\", \"Determinants of pro- vs anti-tumor outcome unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Systematically defined the truncation boundaries required for dominant-negative hyper-IgE syndrome, pinpointing loss of the intracellular recycling motif (782-787) and surface accumulation as the mechanism.\",\n      \"evidence\": \"Comprehensive truncation mutagenesis, surface-accumulation flow cytometry, signaling assays, patient genetics\",\n      \"pmids\": [\"40526438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which surface-retained mutant suppresses WT GP130 not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified FBXO2-mediated K63 ubiquitination as a post-translational requirement for IL6ST/STAT3 activation during decidualization and a target of cadmium toxicity.\",\n      \"evidence\": \"Co-IP ubiquitination, FBXO2 overexpression rescue, in vitro stromal models, in vivo cadmium mouse model\",\n      \"pmids\": [\"41076860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on IL6ST not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed chromatin and RNA-level regulation of IL6ST, including YEATS2/TAF15/KAT5-driven H3K27ac promoter activation and IGF2BP3-mediated m6A mRNA stabilization in a STAT3 feedback loop.\",\n      \"evidence\": \"Co-IP-MS, ChIP, RIP-qPCR, in vitro and in vivo tumor assays\",\n      \"pmids\": [\"40040791\", \"41286950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab cancer-specific findings\", \"Generalizability of feedback loop beyond these tumors untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse post-transcriptional, ubiquitination, and chaperone-mediated autophagy controls of GP130 abundance are integrated with cytokine-specific receptor geometry to set context-dependent STAT3 output in physiology versus disease remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking abundance regulation to signaling geometry\", \"Tissue-specific determinants of pro- vs anti-tumor STAT3 outcomes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 5, 21]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 4, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 17]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 21, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 10, 17]}\n    ],\n    \"complexes\": [\n      \"IL-6 receptor signaling complex (IL-6/IL-6R/GP130)\",\n      \"LIF-GP130-LIFR trimeric complex\",\n      \"IL-6·sIL-6R·sgp130 ternary complex\"\n    ],\n    \"partners\": [\n      \"IL6R\",\n      \"LIFR\",\n      \"HSPA8\",\n      \"LAMP2A\",\n      \"FBXO2\",\n      \"IGF2BP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}