{"gene":"IL10RB","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1998,"finding":"CRF2-4 (IL-10RB) is an essential subunit of the IL-10 receptor complex; mice with CRFB4 gene disrupted by homologous recombination lack responsiveness to IL-10 and develop chronic colitis, recapitulating the IL-10-deficient phenotype.","method":"Homologous recombination knockout mouse, cytokine responsiveness assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and organismal phenotype, replicated by functional IL-10 signaling assays","pmids":["9463407"],"is_preprint":false},{"year":2000,"finding":"IL-10RB (CRF2-4) is a shared signaling component of the IL-22 receptor complex; both CRF2-9 (IL-22R1) and IL-10R2 must be expressed to assemble a functional IL-22 receptor complex, and each chain can independently bind IL-22 but binding to the complex is greater.","method":"Heterologous expression in COS and hamster cells, radiolabeled ligand cross-linking, STAT activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reconstitution in cell lines with multiple orthogonal assays, replicated by independent group same year","pmids":["11035029"],"is_preprint":false},{"year":2000,"finding":"IL-22 signals through a receptor complex consisting of IL-22R and IL-10RB (CRF2-4); cell lines respond to IL-22 by STAT1, STAT3, and STAT5 activation via this receptor complex.","method":"Receptor identification by expression cloning, STAT activation assays, ligand-binding studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — functional reconstitution with STAT signaling readout, replicated by independent group same year","pmids":["10875937"],"is_preprint":false},{"year":2004,"finding":"IL-10R2 is a shared common chain in at least four distinct class II cytokine-receptor complexes (IL-10, IL-22, IL-26, IFN-lambda); activation by any of these cytokines can be blocked with neutralizing antibodies to IL-10R2.","method":"Neutralizing antibody blockade assays, receptor reconstitution experiments","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 — functional blockade with neutralizing antibodies, convergent evidence across multiple cytokine systems","pmids":["15123776"],"is_preprint":false},{"year":2004,"finding":"The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix (around N54), and N-linked glycosylation at N54 (specifically a single fucosylated N-acetyl glucosamine) is required for maximal IL-10R2 binding to IL-22.","method":"Surface plasmon resonance, site-directed mutagenesis, cell-based luciferase assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — SPR binding assays with mutagenesis and cell-based functional validation","pmids":["15327950"],"is_preprint":false},{"year":2004,"finding":"IL-10R2 binds to a surface created by the prior interaction between IL-22 and IL-22R (sequential assembly), further stabilizing the cytokine-receptor complex; IL-10R2 binding is undetectable to IL-22 alone but greatly enhanced in the IL-22/IL-22R complex.","method":"ELISA-based binding assays with biotinylated IL-22 and Fc-fusion receptor ectodomains, sequential addition experiments","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 1 — quantitative in vitro binding assay demonstrating ordered sequential assembly mechanism","pmids":["15120653"],"is_preprint":false},{"year":2006,"finding":"IL-10R1-induced conformational changes in IL-10 regulate IL-10R2 binding and assembly of the ternary IL-10/IL-10R1/IL-10R2 complex; IL-10R2 binding residues on IL-10 are located in helix A and show large structural differences between unbound and IL-10R1-bound forms.","method":"Surface plasmon resonance, cell-based assays, crystal structure comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — SPR combined with structural analysis and cell-based functional assays","pmids":["16982608"],"is_preprint":false},{"year":2008,"finding":"The IL-10R2 binding site on IL-22 is located on helices A, D, and F and loop AB, juxtaposed with but distinct from the IL-22R binding site; comprehensive mutagenesis defined individual amino acid residues required for IL-10R2 binding.","method":"Comprehensive alanine scanning mutagenesis, ELISA, cell-based assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — comprehensive mutagenesis with multiple functional readouts","pmids":["18675824"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the IL-10R2 ectodomain determined at 2.14 Å resolution; alanine scanning identified IL-10R2 residues required for binding; computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes revealed a conserved binding epitope surrounded by two clefts accommodating structural diversity of cytokines.","method":"X-ray crystallography, alanine scanning mutagenesis, computational modeling","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at 2.14 Å with mutagenesis validation","pmids":["20462497"],"is_preprint":false},{"year":2017,"finding":"Both the extracellular and intracellular domains of IL-10R2 influence the conformation of IL-10R1 and are required for transducing IL-10 signals; IL-10R2-associated Tyk2 controls amplitude of STAT3 activation and SOCS3 upregulation but plays only a limited role overall in IL-10-mediated responses.","method":"Bone marrow-derived cells from IL-10R-/- and Tyk2-/- mice, STAT3 phosphorylation assays, TNF-α suppression assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic knockouts (IL-10R2-/- and Tyk2-/-) with multiple cell types and functional readouts","pmids":["29016674"],"is_preprint":false},{"year":2012,"finding":"LGG (Lactobacillus rhamnosus GG) upregulates IL-10R2 mRNA expression in the developing murine colon, leading to enhanced IL-10 receptor-mediated STAT3 phosphorylation, increased SOCS3 expression, and attenuation of proinflammatory cytokines; these effects are blocked by anti-IL-10 receptor antibody.","method":"In vivo probiotic administration, RT-PCR, STAT3 phosphorylation assays, antibody blockade","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular mechanism with antibody blockade confirmation, single lab","pmids":["23272193"],"is_preprint":false},{"year":2021,"finding":"IL-10R2 deficiency in VEO-IBD patient-derived iPSC macrophages abolishes IL-10-induced STAT3 phosphorylation, SOCS3 expression, and anti-inflammatory regulation of LPS-induced cytokines; lentiviral or genome-editing correction of IL-10RB reconstitutes STAT3 signaling and anti-inflammatory responses.","method":"iPSC differentiation, genetic correction by lentiviral gene therapy and CRISPR-mediated safe harbor insertion, STAT3 phosphorylation, SOCS3 expression, cytokine secretion assays","journal":"Journal of personalized medicine","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function genetic approaches with multiple orthogonal mechanistic readouts","pmids":["33804706"],"is_preprint":false},{"year":2024,"finding":"KLK2 (prostate kallikrein-2) cleaves the extracellular N-terminal segment of IL-10R2 (at sequence SYRIF, residues 58-63), reducing IL-10R2 surface expression on bone marrow-derived macrophages and impairing IL-10-mediated anti-inflammatory signaling (decreased suppression of nitric oxide, TNF-α, and IL-12 p40).","method":"Fluorescent peptide substrate assays, flow cytometry (FACS), functional LPS/IFN-γ macrophage assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro enzymatic assay combined with cell-surface loss and functional signaling consequence","pmids":["39106042"],"is_preprint":false},{"year":2018,"finding":"IFN-λ4 inhibits HIV infection of macrophages through signaling via the IFN-λR1/IL-10R2 receptor complex, inducing STAT1 phosphorylation and antiviral interferon-stimulated genes; anti-IFN-λR1/IL-10R2 antibodies compromise this inhibition.","method":"Antibody blockade of receptor complex, STAT1 phosphorylation assays, HIV infection assays in macrophages","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor blockade experiment with defined signaling and antiviral functional readouts, single lab","pmids":["30247785"],"is_preprint":false},{"year":2022,"finding":"IL-10RB overexpression in vitro is associated with increased viral load and activation of immune-related molecular pathways relevant to COVID-19, validating IL-10RB as a functional mediator of host susceptibility.","method":"In vitro IL-10RB overexpression, viral load quantification, molecular pathway analysis","journal":"NPJ genomic medicine","confidence":"Low","confidence_rationale":"Tier 3 — single overexpression experiment without mechanistic pathway placement or receptor-level dissection","pmids":["36064543"],"is_preprint":false},{"year":2025,"finding":"IFNLR1 colocalizes with IL-10R2 after IFN-lambda treatment (detected by Duolink proximity ligation assay); IFNLR1 variant 1 is more rapidly internalized than variant 2, and different variants differentially utilize JAK1/TYK2 to achieve distinct STAT1/STAT2 phosphorylation levels and ISG expression patterns.","method":"Proximity ligation assay, ImageStream flow cytometry, western blotting, JAK inhibitor susceptibility, gene expression profiling in iHeps","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.03.677101"],"is_preprint":true},{"year":2025,"finding":"In zebrafish microglia, il10rb perturbation reduces microglial death and decreases lysosomal acidification (LysoTracker-positive lysosomes) without altering lysosome number or size, placing IL-10RB in a signaling axis that regulates microglial lifespan through lysosomal dynamics.","method":"CRISPR screen in zebrafish, confocal microscopy, LysoTracker staining, v-ATPase inhibition","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic perturbation with defined cellular phenotype and mechanistic follow-up, preprint, zebrafish ortholog","pmids":["bio_10.1101_2025.11.21.689277"],"is_preprint":true}],"current_model":"IL-10RB (CRF2-4) is a shared auxiliary receptor subunit that sequentially engages pre-formed ligand/R1-chain complexes (IL-10/IL-10R1, IL-22/IL-22R1, IL-26/IL-20R1, IFN-λ/IFNLR1) via a conserved ectodomain epitope — whose binding is enabled by R1-induced conformational changes in the ligand — and signals intracellularly through Tyk2 to drive JAK-STAT3 activation, SOCS3 induction, and downstream anti-inflammatory or antiviral responses; loss-of-function mutations abolish IL-10 signaling and cause very early onset inflammatory bowel disease, while the extracellular domain can be proteolytically shed by KLK2 to attenuate IL-10 signaling."},"narrative":{"teleology":[{"year":1998,"claim":"Whether CRF2-4 was functionally required for IL-10 signaling in vivo was unknown; targeted gene disruption showed that CRF2-4-null mice lost IL-10 responsiveness and developed chronic colitis, establishing IL-10RB as an essential IL-10 receptor subunit.","evidence":"Homologous recombination knockout mouse with cytokine responsiveness assays","pmids":["9463407"],"confidence":"High","gaps":["No biochemical mechanism for how IL-10RB contributes to signal transduction was defined","Whether IL-10RB participates in other cytokine receptor complexes was unknown"]},{"year":2000,"claim":"It was unclear whether IL-10RB served additional cytokine systems; reconstitution of IL-22 signaling showed that both IL-22R1 and IL-10RB are required for functional IL-22 receptor assembly and STAT activation, establishing IL-10RB as a shared receptor subunit.","evidence":"Heterologous expression in COS and hamster cells, radiolabeled ligand cross-linking, STAT activation assays, and expression cloning","pmids":["11035029","10875937"],"confidence":"High","gaps":["The full repertoire of cytokines using IL-10RB was not yet defined","Whether IL-10RB binds ligand directly or only in complex was unresolved"]},{"year":2004,"claim":"The breadth of IL-10RB usage and the mechanism of its recruitment were open questions; neutralizing antibody blockade confirmed that IL-10RB is shared among IL-10, IL-22, IL-26, and IFN-λ complexes, while binding studies demonstrated that IL-10RB engages the IL-22/IL-22R1 binary complex sequentially rather than binding free ligand.","evidence":"Neutralizing antibody blockade, SPR, site-directed mutagenesis, ELISA-based sequential binding assays","pmids":["15123776","15327950","15120653"],"confidence":"High","gaps":["Whether sequential assembly also applied to the IL-10 system was not shown","Structural basis of the conserved IL-10RB binding epitope remained undetermined"]},{"year":2006,"claim":"Whether R1-chain-induced conformational changes regulated IL-10RB recruitment was untested for the IL-10 system; SPR and crystal structure comparison showed that IL-10R1 binding reshapes helix A of IL-10 to create the IL-10RB binding site, confirming ordered sequential assembly across cytokine systems.","evidence":"Surface plasmon resonance, crystal structure comparison of free vs. IL-10R1-bound IL-10, cell-based assays","pmids":["16982608"],"confidence":"High","gaps":["No ternary complex crystal structure was available","The contribution of IL-10RB intracellular domain to signaling was unknown"]},{"year":2008,"claim":"The precise IL-10RB contact residues on ligand surfaces needed mapping; comprehensive alanine scanning of IL-22 defined the IL-10RB binding footprint on helices A, D, F and loop AB, delineating it from the IL-22R1 binding site.","evidence":"Alanine scanning mutagenesis, ELISA, cell-based assays","pmids":["18675824"],"confidence":"High","gaps":["Equivalent mapping on IL-10 or IFN-λ was not performed","Structural validation by co-crystal was still lacking"]},{"year":2010,"claim":"No atomic-resolution structure of IL-10RB itself existed; the 2.14 Å crystal structure of the IL-10RB ectodomain, combined with mutagenesis, revealed a conserved binding epitope flanked by flexible clefts that accommodate the structural diversity of its multiple ligand partners.","evidence":"X-ray crystallography at 2.14 Å, alanine scanning mutagenesis, computational ternary complex modeling","pmids":["20462497"],"confidence":"High","gaps":["Experimental ternary complex structures were still modeled computationally","Mechanism of intracellular signal initiation upon IL-10RB engagement remained unclear"]},{"year":2017,"claim":"The signaling contribution of IL-10RB's intracellular domain and its associated kinase Tyk2 were undefined; studies with IL-10R2−/− and Tyk2−/− bone marrow cells showed that IL-10RB influences IL-10R1 conformation and that Tyk2 controls STAT3 phosphorylation amplitude and SOCS3 induction, though Tyk2 is dispensable for some IL-10 responses.","evidence":"Bone marrow-derived macrophages from IL-10R2−/− and Tyk2−/− mice, STAT3 phosphorylation and TNF-α suppression assays","pmids":["29016674"],"confidence":"High","gaps":["Tyk2-independent signaling mechanisms downstream of IL-10RB were not identified","Role of IL-10RB intracellular domain beyond Tyk2 association was unresolved"]},{"year":2018,"claim":"Whether IL-10RB participated in antiviral IFN-λ signaling in primary cells was functionally unconfirmed; antibody blockade of IFN-λR1/IL-10RB impaired IFN-λ4-mediated STAT1 phosphorylation and anti-HIV activity in macrophages, confirming IL-10RB as essential for IFN-λ antiviral signaling.","evidence":"Anti-IFN-λR1/IL-10RB antibody blockade, STAT1 phosphorylation, HIV infection assays in macrophages","pmids":["30247785"],"confidence":"Medium","gaps":["Only IFN-λ4 was tested; generalization to other IFN-λ subtypes was not shown","Single laboratory finding"]},{"year":2021,"claim":"Whether IL-10RB loss-of-function mutations directly cause the VEO-IBD phenotype through defective STAT3/SOCS3 signaling was not demonstrated at the human cellular level; patient iPSC-derived macrophages lacking IL-10RB showed abolished IL-10-STAT3-SOCS3 signaling, which was fully restored by lentiviral or CRISPR-mediated genetic correction.","evidence":"iPSC-derived macrophages from VEO-IBD patients, lentiviral and CRISPR safe-harbor correction, STAT3 phosphorylation and SOCS3 expression assays","pmids":["33804706"],"confidence":"High","gaps":["In vivo gene therapy rescue of IBD has not been demonstrated","Contribution of IL-22 and IFN-λ signaling loss to the disease phenotype was not dissected"]},{"year":2024,"claim":"Whether IL-10RB surface expression is regulated post-translationally was unknown; identification of KLK2-mediated cleavage of the IL-10RB extracellular domain (residues 58–63) demonstrated a proteolytic mechanism that reduces surface IL-10RB and attenuates IL-10 anti-inflammatory signaling.","evidence":"Fluorescent peptide substrate assays, flow cytometry, LPS/IFN-γ macrophage functional assays","pmids":["39106042"],"confidence":"Medium","gaps":["In vivo relevance of KLK2 shedding has not been established","Whether shedding affects IL-22 or IFN-λ signaling was not tested","Whether other proteases also cleave IL-10RB is unknown"]},{"year":null,"claim":"Key unresolved questions include the experimental structure of a complete ternary signaling complex (ligand/R1/IL-10RB), the Tyk2-independent intracellular signaling pathways mediated by IL-10RB, and the physiological relevance of IL-10RB ectodomain shedding in disease settings.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimental ternary complex structure exists","Tyk2-independent signaling downstream of IL-10RB is uncharacterized","In vivo consequences of IL-10RB shedding are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,3,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,12]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"complexes":[],"partners":["IL10RA","IL22RA1","IFNLR1","IL20RA","TYK2","KLK2"],"other_free_text":[]},"mechanistic_narrative":"IL-10RB (also called CRF2-4 or IL-10R2) is a shared class II cytokine receptor subunit that serves as an obligate accessory chain for at least four distinct receptor complexes — those for IL-10, IL-22, IL-26, and IFN-λ — thereby coupling diverse anti-inflammatory and antiviral cytokine signals to JAK-STAT activation [PMID:9463407, PMID:15123776, PMID:30247785]. IL-10RB is recruited to pre-formed ligand/R1-chain binary complexes through a conserved ectodomain epitope; conformational changes induced in the ligand by the R1 chain create the IL-10RB binding site, enforcing a sequential assembly mechanism [PMID:15120653, PMID:16982608, PMID:20462497]. Intracellularly, IL-10RB-associated Tyk2 controls the amplitude of STAT3 phosphorylation and SOCS3 induction, which mediate anti-inflammatory suppression of TNF-α and other pro-inflammatory cytokines; loss-of-function mutations in IL10RB abolish IL-10 signaling and cause very-early-onset inflammatory bowel disease [PMID:29016674, PMID:33804706, PMID:9463407]. The extracellular domain of IL-10RB can be proteolytically shed by KLK2, reducing surface expression and attenuating IL-10-mediated anti-inflammatory signaling [PMID:39106042]."},"prefetch_data":{"uniprot":{"accession":"Q08334","full_name":"Interleukin-10 receptor subunit beta","aliases":["Cytokine receptor class-II member 4","Cytokine receptor family 2 member 4","CRF2-4","Interleukin-10 receptor subunit 2","IL-10R subunit 2","IL-10R2"],"length_aa":325,"mass_kda":37.0,"function":"Shared cell surface receptor required for the activation of five class 2 cytokines: IL10, IL22, IL26, IL28, and IFNL1. The IFNLR1/IL10RB dimer is a receptor for the cytokine ligands IFNL2 and IFNL3 and mediates their antiviral activity. The ligand/receptor complex stimulate the activation of the JAK/STAT signaling pathway leading to the expression of IFN-stimulated genes (ISG), which contribute to the antiviral state","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q08334/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL10RB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL10RB","total_profiled":1310},"omim":[{"mim_id":"615090","title":"INTERFERON, LAMBDA-4; IFNL4","url":"https://www.omim.org/entry/615090"},{"mim_id":"613956","title":"CANDIDIASIS, FAMILIAL, 6; CANDF6","url":"https://www.omim.org/entry/613956"},{"mim_id":"613148","title":"INFLAMMATORY BOWEL DISEASE 28, AUTOSOMAL RECESSIVE; IBD28","url":"https://www.omim.org/entry/613148"},{"mim_id":"612567","title":"INFLAMMATORY BOWEL DISEASE 25, AUTOSOMAL RECESSIVE; IBD25","url":"https://www.omim.org/entry/612567"},{"mim_id":"610424","title":"HEPATITIS B VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/610424"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL10RB"},"hgnc":{"alias_symbol":["CRF2-4","CDW210B","IL-10R2"],"prev_symbol":["CRFB4","D21S58","D21S66"]},"alphafold":{"accession":"Q08334","domains":[{"cath_id":"2.60.40.10","chopping":"26-111","consensus_level":"high","plddt":96.6345,"start":26,"end":111},{"cath_id":"2.60.40.10","chopping":"118-213","consensus_level":"high","plddt":95.5565,"start":118,"end":213}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08334","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08334-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08334-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL10RB","jax_strain_url":"https://www.jax.org/strain/search?query=IL10RB"},"sequence":{"accession":"Q08334","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08334.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08334/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08334"}},"corpus_meta":[{"pmid":"10875937","id":"PMC_10875937","title":"Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10875937","citation_count":440,"is_preprint":false},{"pmid":"11035029","id":"PMC_11035029","title":"Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11035029","citation_count":330,"is_preprint":false},{"pmid":"9463407","id":"PMC_9463407","title":"The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor.","date":"1998","source":"The Journal of experimental 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disrupted by homologous recombination lack responsiveness to IL-10 and develop chronic colitis, recapitulating the IL-10-deficient phenotype.\",\n      \"method\": \"Homologous recombination knockout mouse, cytokine responsiveness assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and organismal phenotype, replicated by functional IL-10 signaling assays\",\n      \"pmids\": [\"9463407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-10RB (CRF2-4) is a shared signaling component of the IL-22 receptor complex; both CRF2-9 (IL-22R1) and IL-10R2 must be expressed to assemble a functional IL-22 receptor complex, and each chain can independently bind IL-22 but binding to the complex is greater.\",\n      \"method\": \"Heterologous expression in COS and hamster cells, radiolabeled ligand cross-linking, STAT activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution in cell lines with multiple orthogonal assays, replicated by independent group same year\",\n      \"pmids\": [\"11035029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-22 signals through a receptor complex consisting of IL-22R and IL-10RB (CRF2-4); cell lines respond to IL-22 by STAT1, STAT3, and STAT5 activation via this receptor complex.\",\n      \"method\": \"Receptor identification by expression cloning, STAT activation assays, ligand-binding studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution with STAT signaling readout, replicated by independent group same year\",\n      \"pmids\": [\"10875937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-10R2 is a shared common chain in at least four distinct class II cytokine-receptor complexes (IL-10, IL-22, IL-26, IFN-lambda); activation by any of these cytokines can be blocked with neutralizing antibodies to IL-10R2.\",\n      \"method\": \"Neutralizing antibody blockade assays, receptor reconstitution experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional blockade with neutralizing antibodies, convergent evidence across multiple cytokine systems\",\n      \"pmids\": [\"15123776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix (around N54), and N-linked glycosylation at N54 (specifically a single fucosylated N-acetyl glucosamine) is required for maximal IL-10R2 binding to IL-22.\",\n      \"method\": \"Surface plasmon resonance, site-directed mutagenesis, cell-based luciferase assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SPR binding assays with mutagenesis and cell-based functional validation\",\n      \"pmids\": [\"15327950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-10R2 binds to a surface created by the prior interaction between IL-22 and IL-22R (sequential assembly), further stabilizing the cytokine-receptor complex; IL-10R2 binding is undetectable to IL-22 alone but greatly enhanced in the IL-22/IL-22R complex.\",\n      \"method\": \"ELISA-based binding assays with biotinylated IL-22 and Fc-fusion receptor ectodomains, sequential addition experiments\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro binding assay demonstrating ordered sequential assembly mechanism\",\n      \"pmids\": [\"15120653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-10R1-induced conformational changes in IL-10 regulate IL-10R2 binding and assembly of the ternary IL-10/IL-10R1/IL-10R2 complex; IL-10R2 binding residues on IL-10 are located in helix A and show large structural differences between unbound and IL-10R1-bound forms.\",\n      \"method\": \"Surface plasmon resonance, cell-based assays, crystal structure comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SPR combined with structural analysis and cell-based functional assays\",\n      \"pmids\": [\"16982608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IL-10R2 binding site on IL-22 is located on helices A, D, and F and loop AB, juxtaposed with but distinct from the IL-22R binding site; comprehensive mutagenesis defined individual amino acid residues required for IL-10R2 binding.\",\n      \"method\": \"Comprehensive alanine scanning mutagenesis, ELISA, cell-based assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — comprehensive mutagenesis with multiple functional readouts\",\n      \"pmids\": [\"18675824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the IL-10R2 ectodomain determined at 2.14 Å resolution; alanine scanning identified IL-10R2 residues required for binding; computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes revealed a conserved binding epitope surrounded by two clefts accommodating structural diversity of cytokines.\",\n      \"method\": \"X-ray crystallography, alanine scanning mutagenesis, computational modeling\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.14 Å with mutagenesis validation\",\n      \"pmids\": [\"20462497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Both the extracellular and intracellular domains of IL-10R2 influence the conformation of IL-10R1 and are required for transducing IL-10 signals; IL-10R2-associated Tyk2 controls amplitude of STAT3 activation and SOCS3 upregulation but plays only a limited role overall in IL-10-mediated responses.\",\n      \"method\": \"Bone marrow-derived cells from IL-10R-/- and Tyk2-/- mice, STAT3 phosphorylation assays, TNF-α suppression assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts (IL-10R2-/- and Tyk2-/-) with multiple cell types and functional readouts\",\n      \"pmids\": [\"29016674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGG (Lactobacillus rhamnosus GG) upregulates IL-10R2 mRNA expression in the developing murine colon, leading to enhanced IL-10 receptor-mediated STAT3 phosphorylation, increased SOCS3 expression, and attenuation of proinflammatory cytokines; these effects are blocked by anti-IL-10 receptor antibody.\",\n      \"method\": \"In vivo probiotic administration, RT-PCR, STAT3 phosphorylation assays, antibody blockade\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular mechanism with antibody blockade confirmation, single lab\",\n      \"pmids\": [\"23272193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-10R2 deficiency in VEO-IBD patient-derived iPSC macrophages abolishes IL-10-induced STAT3 phosphorylation, SOCS3 expression, and anti-inflammatory regulation of LPS-induced cytokines; lentiviral or genome-editing correction of IL-10RB reconstitutes STAT3 signaling and anti-inflammatory responses.\",\n      \"method\": \"iPSC differentiation, genetic correction by lentiviral gene therapy and CRISPR-mediated safe harbor insertion, STAT3 phosphorylation, SOCS3 expression, cytokine secretion assays\",\n      \"journal\": \"Journal of personalized medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function genetic approaches with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"33804706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLK2 (prostate kallikrein-2) cleaves the extracellular N-terminal segment of IL-10R2 (at sequence SYRIF, residues 58-63), reducing IL-10R2 surface expression on bone marrow-derived macrophages and impairing IL-10-mediated anti-inflammatory signaling (decreased suppression of nitric oxide, TNF-α, and IL-12 p40).\",\n      \"method\": \"Fluorescent peptide substrate assays, flow cytometry (FACS), functional LPS/IFN-γ macrophage assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro enzymatic assay combined with cell-surface loss and functional signaling consequence\",\n      \"pmids\": [\"39106042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFN-λ4 inhibits HIV infection of macrophages through signaling via the IFN-λR1/IL-10R2 receptor complex, inducing STAT1 phosphorylation and antiviral interferon-stimulated genes; anti-IFN-λR1/IL-10R2 antibodies compromise this inhibition.\",\n      \"method\": \"Antibody blockade of receptor complex, STAT1 phosphorylation assays, HIV infection assays in macrophages\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor blockade experiment with defined signaling and antiviral functional readouts, single lab\",\n      \"pmids\": [\"30247785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-10RB overexpression in vitro is associated with increased viral load and activation of immune-related molecular pathways relevant to COVID-19, validating IL-10RB as a functional mediator of host susceptibility.\",\n      \"method\": \"In vitro IL-10RB overexpression, viral load quantification, molecular pathway analysis\",\n      \"journal\": \"NPJ genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single overexpression experiment without mechanistic pathway placement or receptor-level dissection\",\n      \"pmids\": [\"36064543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFNLR1 colocalizes with IL-10R2 after IFN-lambda treatment (detected by Duolink proximity ligation assay); IFNLR1 variant 1 is more rapidly internalized than variant 2, and different variants differentially utilize JAK1/TYK2 to achieve distinct STAT1/STAT2 phosphorylation levels and ISG expression patterns.\",\n      \"method\": \"Proximity ligation assay, ImageStream flow cytometry, western blotting, JAK inhibitor susceptibility, gene expression profiling in iHeps\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.03.677101\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish microglia, il10rb perturbation reduces microglial death and decreases lysosomal acidification (LysoTracker-positive lysosomes) without altering lysosome number or size, placing IL-10RB in a signaling axis that regulates microglial lifespan through lysosomal dynamics.\",\n      \"method\": \"CRISPR screen in zebrafish, confocal microscopy, LysoTracker staining, v-ATPase inhibition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic perturbation with defined cellular phenotype and mechanistic follow-up, preprint, zebrafish ortholog\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689277\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL-10RB (CRF2-4) is a shared auxiliary receptor subunit that sequentially engages pre-formed ligand/R1-chain complexes (IL-10/IL-10R1, IL-22/IL-22R1, IL-26/IL-20R1, IFN-λ/IFNLR1) via a conserved ectodomain epitope — whose binding is enabled by R1-induced conformational changes in the ligand — and signals intracellularly through Tyk2 to drive JAK-STAT3 activation, SOCS3 induction, and downstream anti-inflammatory or antiviral responses; loss-of-function mutations abolish IL-10 signaling and cause very early onset inflammatory bowel disease, while the extracellular domain can be proteolytically shed by KLK2 to attenuate IL-10 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-10RB (also called CRF2-4 or IL-10R2) is a shared class II cytokine receptor subunit that serves as an obligate accessory chain for at least four distinct receptor complexes — those for IL-10, IL-22, IL-26, and IFN-λ — thereby coupling diverse anti-inflammatory and antiviral cytokine signals to JAK-STAT activation [PMID:9463407, PMID:15123776, PMID:30247785]. IL-10RB is recruited to pre-formed ligand/R1-chain binary complexes through a conserved ectodomain epitope; conformational changes induced in the ligand by the R1 chain create the IL-10RB binding site, enforcing a sequential assembly mechanism [PMID:15120653, PMID:16982608, PMID:20462497]. Intracellularly, IL-10RB-associated Tyk2 controls the amplitude of STAT3 phosphorylation and SOCS3 induction, which mediate anti-inflammatory suppression of TNF-α and other pro-inflammatory cytokines; loss-of-function mutations in IL10RB abolish IL-10 signaling and cause very-early-onset inflammatory bowel disease [PMID:29016674, PMID:33804706, PMID:9463407]. The extracellular domain of IL-10RB can be proteolytically shed by KLK2, reducing surface expression and attenuating IL-10-mediated anti-inflammatory signaling [PMID:39106042].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Whether CRF2-4 was functionally required for IL-10 signaling in vivo was unknown; targeted gene disruption showed that CRF2-4-null mice lost IL-10 responsiveness and developed chronic colitis, establishing IL-10RB as an essential IL-10 receptor subunit.\",\n      \"evidence\": \"Homologous recombination knockout mouse with cytokine responsiveness assays\",\n      \"pmids\": [\"9463407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical mechanism for how IL-10RB contributes to signal transduction was defined\", \"Whether IL-10RB participates in other cytokine receptor complexes was unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"It was unclear whether IL-10RB served additional cytokine systems; reconstitution of IL-22 signaling showed that both IL-22R1 and IL-10RB are required for functional IL-22 receptor assembly and STAT activation, establishing IL-10RB as a shared receptor subunit.\",\n      \"evidence\": \"Heterologous expression in COS and hamster cells, radiolabeled ligand cross-linking, STAT activation assays, and expression cloning\",\n      \"pmids\": [\"11035029\", \"10875937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The full repertoire of cytokines using IL-10RB was not yet defined\", \"Whether IL-10RB binds ligand directly or only in complex was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The breadth of IL-10RB usage and the mechanism of its recruitment were open questions; neutralizing antibody blockade confirmed that IL-10RB is shared among IL-10, IL-22, IL-26, and IFN-λ complexes, while binding studies demonstrated that IL-10RB engages the IL-22/IL-22R1 binary complex sequentially rather than binding free ligand.\",\n      \"evidence\": \"Neutralizing antibody blockade, SPR, site-directed mutagenesis, ELISA-based sequential binding assays\",\n      \"pmids\": [\"15123776\", \"15327950\", \"15120653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sequential assembly also applied to the IL-10 system was not shown\", \"Structural basis of the conserved IL-10RB binding epitope remained undetermined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether R1-chain-induced conformational changes regulated IL-10RB recruitment was untested for the IL-10 system; SPR and crystal structure comparison showed that IL-10R1 binding reshapes helix A of IL-10 to create the IL-10RB binding site, confirming ordered sequential assembly across cytokine systems.\",\n      \"evidence\": \"Surface plasmon resonance, crystal structure comparison of free vs. IL-10R1-bound IL-10, cell-based assays\",\n      \"pmids\": [\"16982608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ternary complex crystal structure was available\", \"The contribution of IL-10RB intracellular domain to signaling was unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The precise IL-10RB contact residues on ligand surfaces needed mapping; comprehensive alanine scanning of IL-22 defined the IL-10RB binding footprint on helices A, D, F and loop AB, delineating it from the IL-22R1 binding site.\",\n      \"evidence\": \"Alanine scanning mutagenesis, ELISA, cell-based assays\",\n      \"pmids\": [\"18675824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Equivalent mapping on IL-10 or IFN-λ was not performed\", \"Structural validation by co-crystal was still lacking\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"No atomic-resolution structure of IL-10RB itself existed; the 2.14 Å crystal structure of the IL-10RB ectodomain, combined with mutagenesis, revealed a conserved binding epitope flanked by flexible clefts that accommodate the structural diversity of its multiple ligand partners.\",\n      \"evidence\": \"X-ray crystallography at 2.14 Å, alanine scanning mutagenesis, computational ternary complex modeling\",\n      \"pmids\": [\"20462497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Experimental ternary complex structures were still modeled computationally\", \"Mechanism of intracellular signal initiation upon IL-10RB engagement remained unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The signaling contribution of IL-10RB's intracellular domain and its associated kinase Tyk2 were undefined; studies with IL-10R2−/− and Tyk2−/− bone marrow cells showed that IL-10RB influences IL-10R1 conformation and that Tyk2 controls STAT3 phosphorylation amplitude and SOCS3 induction, though Tyk2 is dispensable for some IL-10 responses.\",\n      \"evidence\": \"Bone marrow-derived macrophages from IL-10R2−/− and Tyk2−/− mice, STAT3 phosphorylation and TNF-α suppression assays\",\n      \"pmids\": [\"29016674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tyk2-independent signaling mechanisms downstream of IL-10RB were not identified\", \"Role of IL-10RB intracellular domain beyond Tyk2 association was unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether IL-10RB participated in antiviral IFN-λ signaling in primary cells was functionally unconfirmed; antibody blockade of IFN-λR1/IL-10RB impaired IFN-λ4-mediated STAT1 phosphorylation and anti-HIV activity in macrophages, confirming IL-10RB as essential for IFN-λ antiviral signaling.\",\n      \"evidence\": \"Anti-IFN-λR1/IL-10RB antibody blockade, STAT1 phosphorylation, HIV infection assays in macrophages\",\n      \"pmids\": [\"30247785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only IFN-λ4 was tested; generalization to other IFN-λ subtypes was not shown\", \"Single laboratory finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether IL-10RB loss-of-function mutations directly cause the VEO-IBD phenotype through defective STAT3/SOCS3 signaling was not demonstrated at the human cellular level; patient iPSC-derived macrophages lacking IL-10RB showed abolished IL-10-STAT3-SOCS3 signaling, which was fully restored by lentiviral or CRISPR-mediated genetic correction.\",\n      \"evidence\": \"iPSC-derived macrophages from VEO-IBD patients, lentiviral and CRISPR safe-harbor correction, STAT3 phosphorylation and SOCS3 expression assays\",\n      \"pmids\": [\"33804706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo gene therapy rescue of IBD has not been demonstrated\", \"Contribution of IL-22 and IFN-λ signaling loss to the disease phenotype was not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether IL-10RB surface expression is regulated post-translationally was unknown; identification of KLK2-mediated cleavage of the IL-10RB extracellular domain (residues 58–63) demonstrated a proteolytic mechanism that reduces surface IL-10RB and attenuates IL-10 anti-inflammatory signaling.\",\n      \"evidence\": \"Fluorescent peptide substrate assays, flow cytometry, LPS/IFN-γ macrophage functional assays\",\n      \"pmids\": [\"39106042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of KLK2 shedding has not been established\", \"Whether shedding affects IL-22 or IFN-λ signaling was not tested\", \"Whether other proteases also cleave IL-10RB is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the experimental structure of a complete ternary signaling complex (ligand/R1/IL-10RB), the Tyk2-independent intracellular signaling pathways mediated by IL-10RB, and the physiological relevance of IL-10RB ectodomain shedding in disease settings.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental ternary complex structure exists\", \"Tyk2-independent signaling downstream of IL-10RB is uncharacterized\", \"In vivo consequences of IL-10RB shedding are unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL10RA\", \"IL22RA1\", \"IFNLR1\", \"IL20RA\", \"TYK2\", \"KLK2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error in the pathway section — I used a GO term instead of a Reactome term. Let me correct that.\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-10RB (also called CRF2-4 or IL-10R2) is a shared class II cytokine receptor subunit that serves as an obligate accessory chain for at least four distinct receptor complexes — those for IL-10, IL-22, IL-26, and IFN-λ — thereby coupling diverse anti-inflammatory and antiviral cytokine signals to JAK-STAT activation [PMID:9463407, PMID:15123776, PMID:30247785]. IL-10RB is recruited to pre-formed ligand/R1-chain binary complexes through a conserved ectodomain epitope; conformational changes induced in the ligand by the R1 chain create the IL-10RB binding site, enforcing a sequential assembly mechanism [PMID:15120653, PMID:16982608, PMID:20462497]. Intracellularly, IL-10RB-associated Tyk2 controls the amplitude of STAT3 phosphorylation and SOCS3 induction, which mediate anti-inflammatory suppression of TNF-α and other pro-inflammatory cytokines; loss-of-function mutations in IL10RB abolish IL-10 signaling and cause very-early-onset inflammatory bowel disease [PMID:29016674, PMID:33804706, PMID:9463407]. The extracellular domain of IL-10RB can be proteolytically shed by KLK2, reducing surface expression and attenuating IL-10-mediated anti-inflammatory signaling [PMID:39106042].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Whether CRF2-4 was functionally required for IL-10 signaling in vivo was unknown; targeted gene disruption showed that CRF2-4-null mice lost IL-10 responsiveness and developed chronic colitis, establishing IL-10RB as an essential IL-10 receptor subunit.\",\n      \"evidence\": \"Homologous recombination knockout mouse with cytokine responsiveness assays\",\n      \"pmids\": [\"9463407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical mechanism for how IL-10RB contributes to signal transduction was defined\", \"Whether IL-10RB participates in other cytokine receptor complexes was unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"It was unclear whether IL-10RB served additional cytokine systems; reconstitution of IL-22 signaling showed that both IL-22R1 and IL-10RB are required for functional IL-22 receptor assembly and STAT activation, establishing IL-10RB as a shared receptor subunit.\",\n      \"evidence\": \"Heterologous expression in COS and hamster cells, radiolabeled ligand cross-linking, STAT activation assays, and expression cloning\",\n      \"pmids\": [\"11035029\", \"10875937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The full repertoire of cytokines using IL-10RB was not yet defined\", \"Whether IL-10RB binds ligand directly or only in complex was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The breadth of IL-10RB usage and the mechanism of its recruitment were open questions; neutralizing antibody blockade confirmed that IL-10RB is shared among IL-10, IL-22, IL-26, and IFN-λ complexes, while binding studies demonstrated that IL-10RB engages the IL-22/IL-22R1 binary complex sequentially rather than binding free ligand.\",\n      \"evidence\": \"Neutralizing antibody blockade, SPR, site-directed mutagenesis, ELISA-based sequential binding assays\",\n      \"pmids\": [\"15123776\", \"15327950\", \"15120653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sequential assembly also applied to the IL-10 system was not shown\", \"Structural basis of the conserved IL-10RB binding epitope remained undetermined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether R1-chain-induced conformational changes regulated IL-10RB recruitment was untested for the IL-10 system; SPR and crystal structure comparison showed that IL-10R1 binding reshapes helix A of IL-10 to create the IL-10RB binding site, confirming ordered sequential assembly across cytokine systems.\",\n      \"evidence\": \"Surface plasmon resonance, crystal structure comparison of free vs. IL-10R1-bound IL-10, cell-based assays\",\n      \"pmids\": [\"16982608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ternary complex crystal structure was available\", \"The contribution of IL-10RB intracellular domain to signaling was unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The precise IL-10RB contact residues on ligand surfaces needed mapping; comprehensive alanine scanning of IL-22 defined the IL-10RB binding footprint on helices A, D, F and loop AB, delineating it from the IL-22R1 binding site.\",\n      \"evidence\": \"Alanine scanning mutagenesis, ELISA, cell-based assays\",\n      \"pmids\": [\"18675824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Equivalent mapping on IL-10 or IFN-λ was not performed\", \"Structural validation by co-crystal was still lacking\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"No atomic-resolution structure of IL-10RB itself existed; the 2.14 Å crystal structure of the IL-10RB ectodomain, combined with mutagenesis, revealed a conserved binding epitope flanked by flexible clefts that accommodate the structural diversity of its multiple ligand partners.\",\n      \"evidence\": \"X-ray crystallography at 2.14 Å, alanine scanning mutagenesis, computational ternary complex modeling\",\n      \"pmids\": [\"20462497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Experimental ternary complex structures were still modeled computationally\", \"Mechanism of intracellular signal initiation upon IL-10RB engagement remained unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The signaling contribution of IL-10RB's intracellular domain and its associated kinase Tyk2 were undefined; studies with IL-10R2−/− and Tyk2−/− bone marrow cells showed that IL-10RB influences IL-10R1 conformation and that Tyk2 controls STAT3 phosphorylation amplitude and SOCS3 induction, though Tyk2 is dispensable for some IL-10 responses.\",\n      \"evidence\": \"Bone marrow-derived macrophages from IL-10R2−/− and Tyk2−/− mice, STAT3 phosphorylation and TNF-α suppression assays\",\n      \"pmids\": [\"29016674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tyk2-independent signaling mechanisms downstream of IL-10RB were not identified\", \"Role of IL-10RB intracellular domain beyond Tyk2 association was unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether IL-10RB participated in antiviral IFN-λ signaling in primary cells was functionally unconfirmed; antibody blockade of IFN-λR1/IL-10RB impaired IFN-λ4-mediated STAT1 phosphorylation and anti-HIV activity in macrophages, confirming IL-10RB as essential for IFN-λ antiviral signaling.\",\n      \"evidence\": \"Anti-IFN-λR1/IL-10RB antibody blockade, STAT1 phosphorylation, HIV infection assays in macrophages\",\n      \"pmids\": [\"30247785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only IFN-λ4 was tested; generalization to other IFN-λ subtypes was not shown\", \"Single laboratory finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether IL-10RB loss-of-function mutations directly cause the VEO-IBD phenotype through defective STAT3/SOCS3 signaling was not demonstrated at the human cellular level; patient iPSC-derived macrophages lacking IL-10RB showed abolished IL-10-STAT3-SOCS3 signaling, which was fully restored by lentiviral or CRISPR-mediated genetic correction.\",\n      \"evidence\": \"iPSC-derived macrophages from VEO-IBD patients, lentiviral and CRISPR safe-harbor correction, STAT3 phosphorylation and SOCS3 expression assays\",\n      \"pmids\": [\"33804706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo gene therapy rescue of IBD has not been demonstrated\", \"Contribution of IL-22 and IFN-λ signaling loss to the disease phenotype was not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether IL-10RB surface expression is regulated post-translationally was unknown; identification of KLK2-mediated cleavage of the IL-10RB extracellular domain (residues 58–63) demonstrated a proteolytic mechanism that reduces surface IL-10RB and attenuates IL-10 anti-inflammatory signaling.\",\n      \"evidence\": \"Fluorescent peptide substrate assays, flow cytometry, LPS/IFN-γ macrophage functional assays\",\n      \"pmids\": [\"39106042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of KLK2 shedding has not been established\", \"Whether shedding affects IL-22 or IFN-λ signaling was not tested\", \"Whether other proteases also cleave IL-10RB is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the experimental structure of a complete ternary signaling complex (ligand/R1/IL-10RB), the Tyk2-independent intracellular signaling pathways mediated by IL-10RB, and the physiological relevance of IL-10RB ectodomain shedding in disease settings.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental ternary complex structure exists\", \"Tyk2-independent signaling downstream of IL-10RB is uncharacterized\", \"In vivo consequences of IL-10RB shedding are unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 9, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 6, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL10RA\", \"IL22RA1\", \"IFNLR1\", \"IL20RA\", \"TYK2\", \"KLK2\"],\n    \"other_free_text\": []\n  }\n}\n```"}