{"gene":"IL10RB","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1998,"finding":"CRF2-4 (IL10RB) is an essential subunit of the IL-10 receptor complex: mice with homozygous disruption of the CRFB4 gene lose responsiveness to IL-10 but retain normal responsiveness to type I and type II interferons, and develop chronic colitis recapitulating the IL-10-deficient phenotype.","method":"Homologous recombination gene knockout in mice; cytokine responsiveness assays; histopathological analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined cellular and systemic phenotype, mechanistically placing IL10RB as an obligate IL-10 receptor subunit; replicated conceptually by multiple subsequent studies","pmids":["9463407"],"is_preprint":false},{"year":2000,"finding":"IL-22 signals through a receptor complex consisting of CRF2-4 (IL10RB) and a novel receptor chain (IL-22R/CRF2-9); CRF2-4 alone can bind IL-22 but both chains are required for functional signaling; IL-22 activates STATs 1, 3, and 5.","method":"Receptor expression in COS and hamster cells; STAT activation assays; radiolabeled cytokine cross-linking/binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent papers (PMID 10875937 and 11035029) using cell-based functional assays and direct binding studies establish IL10RB as a shared signaling subunit for IL-22","pmids":["10875937","11035029"],"is_preprint":false},{"year":2000,"finding":"IL10RB (IL-10R2) is a shared common chain of both the IL-10 and IL-22 (IL-TIF) receptor complexes; each chain (CRF2-9 and IL-10R2) can independently bind IL-TIF, but binding affinity is greater when both chains form the complete receptor complex; the CRF2-9 chain is responsible for STAT recruitment.","method":"Receptor reconstitution in hamster and COS cells; radiolabeled cytokine cross-linking; STAT activation assays; intracellular domain substitution experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstitution in multiple cell lines, direct binding studies, domain-swap mutagenesis establishing distinct roles of each receptor chain","pmids":["11035029"],"is_preprint":false},{"year":2004,"finding":"IL-10R2 (IL10RB) is a shared component of at least four distinct class II cytokine receptor complexes (IL-10, IL-22, IL-26, and IFN-lambda); neutralizing antibodies to the IL-10R2 chain block signaling by all four cytokines; IL-10R2 engagement occurs after the ligand binds its R1 chain, triggered by a conformational change.","method":"Neutralizing antibody blockade of cytokine signaling; receptor complex characterization; cell-based signaling assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blockade experiments across multiple cytokine systems, single review-style paper but with direct experimental support cited","pmids":["15123776"],"is_preprint":false},{"year":2004,"finding":"The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix (helix A) and requires N-linked glycosylation at asparagine 54; a single fucosylated N-acetyl glucosamine at N54 is required for maximal IL-10R2 binding, and IL-22 mutants with reduced IL-10R2 binding show correspondingly reduced biological activity.","method":"Surface plasmon resonance (SPR); site-directed mutagenesis; glycosylation characterization; cell-based luciferase reporter assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro SPR binding assays with mutagenesis and cell-based functional validation in a single rigorous study","pmids":["15327950"],"is_preprint":false},{"year":2004,"finding":"IL-10R2 (IL10RB) binds to a surface created by the interaction between IL-22 and IL-22R, thereby further stabilizing the cytokine-receptor complex; IL-10R2 has undetectable affinity for IL-22 alone but substantially greater affinity for IL-22/IL-22R complexes.","method":"ELISA-based binding assays with biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments with receptor homodimers","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays with receptor fusion proteins establishing sequential assembly mechanism, single lab","pmids":["15120653"],"is_preprint":false},{"year":2006,"finding":"Assembly of the IL-10 ternary signaling complex (IL-10/IL-10R1/IL-10R2) is sequential: IL-10 first binds IL-10R1, which induces conformational changes in helix A of IL-10 that create the IL-10R2 binding site; critical IL-10R2 binding residues are located in helix A adjacent to the IL-10R1 recognition surface.","method":"Surface plasmon resonance (SPR); cell-based signaling assays; comparison with IL-10/IL-10R1 crystal structures","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SPR binding measurements combined with structural analysis and cell-based validation, establishing conformational mechanism of sequential receptor assembly","pmids":["16982608"],"is_preprint":false},{"year":2008,"finding":"The IL-10R2 and IL-22R binding sites on IL-22 are topologically juxtaposed on adjacent and overlapping surfaces (helices A, D, F and loop AB); comprehensive mutagenesis identified amino acid residues individually important for IL-10R2 binding, considerably expanding the defined IL-10R2 binding surface on IL-22.","method":"Comprehensive site-directed mutagenesis; ELISA cell-based assays; structural modeling","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive mutagenesis combined with cell-based binding assays and structural methods, single lab","pmids":["18675824"],"is_preprint":false},{"year":2010,"finding":"The crystal structure of the IL-10R2 ectodomain at 2.14 Å resolution reveals a conserved binding epitope surrounded by two clefts that accommodate the structural and chemical diversity of different cytokine partners; alanine scanning identified IL-10R2 residues required for cytokine binding, and computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes were derived.","method":"X-ray crystallography at 2.14 Å; alanine scanning mutagenesis; computational docking/modeling","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination combined with functional mutagenesis providing structural mechanism of promiscuous receptor binding","pmids":["20462497"],"is_preprint":false},{"year":2017,"finding":"Both the extracellular and intracellular domains of IL-10R2 (IL10RB) are required for transducing IL-10 signals; the intracellular domain of IL-10R2 influences the conformation of IL-10R1; IL-10-mediated responses depend on both IL-10R1 and IL-10R2 in dendritic cells, macrophages, and mast cells; IL-10R2-associated kinase Tyk2 controls the amplitude of STAT3 activation and SOCS3 upregulation but plays only a limited role in overall IL-10 responses.","method":"Bone marrow-derived cells from IL-10R-/- and Tyk2-/- mice; STAT3 phosphorylation assays; SOCS3 expression; LPS-induced TNF-α cytokine assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic knockouts with multiple orthogonal cellular readouts establishing distinct functional contributions of IL-10R2 extracellular and intracellular domains","pmids":["29016674"],"is_preprint":false},{"year":2012,"finding":"Probiotic LGG upregulates IL-10R2 (IL10RB) subunit expression in developing murine colon, leading to enhanced IL-10 receptor-mediated signaling including increased STAT3 phosphorylation and SOCS3 expression; antibody-mediated blockade of the IL-10 receptor abrogated LGG-dependent reductions in TNF-α and MIP-2.","method":"Real-time PCR; STAT3 phosphorylation assays; antibody blockade of IL-10 receptor; murine model of intestinal injury","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with receptor blockade establishing functional link between IL-10R2 upregulation and downstream STAT3/SOCS3 signaling, single lab","pmids":["23272193"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function mutation in IL10RB abolishes IL-10-induced STAT3 phosphorylation and SOCS3 expression in iPSC-derived macrophages, preventing IL-10-mediated suppression of LPS-induced cytokine secretion (IL-6, TNF-α); lentiviral gene correction or genome editing of IL10RB reconstitutes IL-10-inducible STAT3 phosphorylation, SOCS3 expression, and anti-inflammatory regulation.","method":"iPSC differentiation into macrophages; STAT3 phosphorylation assays; SOCS3 expression; cytokine secretion assays; lentiviral gene therapy and AAVS1 safe harbor genome editing","journal":"Journal of personalized medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function (gene correction) in patient-derived iPSC-derived macrophages with multiple orthogonal functional readouts establishing causal role of IL10RB in IL-10/STAT3/SOCS3 signaling axis","pmids":["33804706"],"is_preprint":false},{"year":2018,"finding":"IFN-λ4 inhibits HIV infection of macrophages through signaling of the IFN-λR1/IL-10R2 receptor complex; antibodies against IFN-λR1/IL-10R2 compromise IFN-λ4-mediated HIV inhibition; IFN-λ4 enhances STAT1 phosphorylation and induces antiviral interferon-stimulated genes through this receptor complex.","method":"Antibody blockade of receptor complex; STAT1 phosphorylation assays; antiviral gene expression assays; HIV infection of macrophages","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — antibody blockade establishing IL-10R2 requirement for IFN-λ4 antiviral signaling, single lab, single method per finding","pmids":["30247785"],"is_preprint":false},{"year":2022,"finding":"IL10RB is identified as a receptor subunit for IFN-υ (type IV interferon) together with IFN-υR1; IFN-υR1/IL-10R2 receptor complex mediates IFN-υ-stimulated gene expression and antiviral activity in zebrafish and Xenopus; the receptor of IFN-υ was verified as IFN-υR1 and IL-10R2 using a chimeric receptor approach.","method":"Chimeric receptor approach in HEK293 cells; ISG expression assays; antiviral activity assays in zebrafish and Xenopus laevis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — chimeric receptor functional reconstitution combined with in vivo antiviral assays in two vertebrate models establishing IL10RB as receptor subunit for type IV IFN","pmids":["35194032"],"is_preprint":false},{"year":2024,"finding":"The extracellular domain of IL-10R2 (IL10RB) is a substrate for KLK2 (prostate kallikrein-2), which cleaves the sequence SYRIF at positions 58-63 of IL-10R2; KLK2 treatment reduces surface IL-10R2 expression on bone marrow-derived macrophages and significantly reduces IL-10-mediated inhibition of inflammatory responses (nitric oxide, TNF-α, IL-12 p40) to LPS/IFN-γ.","method":"Fluorescence resonance energy transfer peptide library assays; flow cytometry (FACS) of cell surface IL-10R2; in vitro macrophage stimulation with LPS/IFN-γ and IL-10; comparison with KLK3 (negative control)","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic cleavage assay with functional consequence on IL-10 signaling in primary macrophages, single lab with negative control","pmids":["39106042"],"is_preprint":false},{"year":2025,"finding":"il10rb perturbation in zebrafish reduces microglial death and decreases lysosomal acidification (reduced LysoTracker-positive lysosomes) without altering lysosome number or size, placing IL10RB in a signaling axis that controls microglial lifespan through lysosomal pH regulation; perturbation of il10, il10rb, and downstream JAK/STAT molecules all reduced microglial death.","method":"CRISPR screen in zebrafish using robotic confocal microscope; LysoTracker live imaging; genetic epistasis with JAK/STAT pathway genes; v-ATPase inhibition experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-based genetic screen with in vivo imaging and lysosomal functional readouts; preprint, single lab","pmids":["bio_10.1101_2025.11.21.689277"],"is_preprint":true},{"year":2024,"finding":"IL10RB overexpression in cancer cells undergoing EMT (driven by snail) enhances cellular adhesion, invasiveness, and chemoresistance; anti-IL10RB blocking monoclonal antibody attenuates these refractory properties and induces anti-tumor immunity in mouse tumor models; combining anti-IL10RB and anti-PD1 therapy has synergistic effects on tumor disappearance.","method":"GeneChip microarray; in vitro adhesion, invasion, and chemoresistance assays in cancer cells; mouse orthotopic tumor models; anti-IL10RB blocking mAb treatment","journal":"BJC reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro functional assays and mouse tumor model with blocking antibody establishing IL10RB role in EMT-driven cancer cell properties, single lab","pmids":["41826681"],"is_preprint":false}],"current_model":"IL10RB (CRF2-4/IL-10R2) is a broadly expressed, obligate shared signaling subunit of at least five class II cytokine receptor complexes (for IL-10, IL-22, IL-26, IFN-λ, and IFN-υ/type IV IFN); it engages these complexes secondarily after each ligand binds its primary R1 receptor chain (a conformational change-dependent step), contributes both extracellular and intracellular domains to receptor activation, associates intracellularly with Tyk2 to modulate STAT3 amplitude, and is required for IL-10-induced STAT3 phosphorylation and SOCS3 upregulation that underlies IL-10's anti-inflammatory actions; its crystal structure reveals a conserved but adaptable binding epitope accommodating diverse cytokine partners through two flanking clefts."},"narrative":{"mechanistic_narrative":"IL10RB (CRF2-4/IL-10R2) is an obligate, broadly shared signaling subunit of multiple class II cytokine receptor complexes, required to transduce the anti-inflammatory and antiviral programs of its cytokine partners [PMID:9463407, PMID:15123776]. Genetic disruption abolishes IL-10 responsiveness while sparing type I and type II interferon signaling, and produces chronic colitis recapitulating IL-10 deficiency, establishing IL10RB as non-redundant in the IL-10 axis [PMID:9463407]. Beyond IL-10 it serves as the common second chain partnering distinct primary R1 receptors for IL-22, IL-26, IFN-λ, and the IFN-υ/type IV IFN system, and neutralizing the IL-10R2 chain blocks signaling by all of these cytokines [PMID:10875937, PMID:11035029, PMID:15123776, PMID:30247785, PMID:35194032]. Receptor assembly is sequential and conformation-dependent: IL10RB has negligible affinity for free cytokine and instead docks onto a composite surface formed only after the ligand engages its R1 chain, which remodels the cytokine (notably helix A of IL-10 and IL-22) to create the IL-10R2 epitope [PMID:15120653, PMID:16982608]. Its crystal structure reveals a conserved binding epitope flanked by two clefts that accommodate the chemical and structural diversity of its many cytokine partners [PMID:20462497]. Both the extracellular and intracellular domains of IL-10R2 are required for signal transduction; the intracellular domain shapes IL-10R1 conformation and the IL-10R2-associated kinase Tyk2 controls the amplitude of STAT3 phosphorylation and SOCS3 upregulation, the core node of IL-10's anti-inflammatory output [PMID:29016674]. Loss-of-function mutation in IL10RB abolishes IL-10-induced STAT3 phosphorylation and SOCS3 expression in human macrophages, and gene correction restores anti-inflammatory regulation, demonstrating a causal requirement for IL10RB in this axis [PMID:33804706]. Surface availability of IL-10R2 is post-translationally regulated: the protease KLK2 cleaves the IL-10R2 ectodomain (SYRIF, residues 58–63), reducing surface receptor and dampening IL-10 signaling [PMID:39106042].","teleology":[{"year":1998,"claim":"Established that IL10RB is a non-redundant subunit of the IL-10 receptor, answering whether this orphan class II chain has a defined ligand system and physiological role.","evidence":"Homozygous CRFB4 gene knockout in mice with cytokine responsiveness and histopathology","pmids":["9463407"],"confidence":"High","gaps":["Did not define the molecular partner chain (IL-10R1) interaction mechanism","Did not address whether the chain is shared by other cytokines"]},{"year":2000,"claim":"Showed that IL10RB is a shared chain serving IL-22 in addition to IL-10, reframing it as a common signaling subunit rather than an IL-10-specific receptor.","evidence":"Receptor reconstitution in COS/hamster cells, radiolabeled cytokine cross-linking, STAT activation and intracellular-domain swap assays","pmids":["10875937","11035029"],"confidence":"High","gaps":["Did not establish the order of chain assembly","Did not resolve which residues mediate IL10RB binding"]},{"year":2004,"claim":"Extended the shared-chain model to four cytokine systems and introduced the sequential, conformation-triggered assembly mechanism, answering how one chain can serve diverse ligands.","evidence":"Neutralizing antibody blockade across IL-10, IL-22, IL-26 and IFN-λ signaling; ELISA and SPR binding with mutagenesis on IL-22","pmids":["15123776","15327950","15120653"],"confidence":"Medium","gaps":["Assembly mechanism inferred from binding kinetics rather than direct structure","Glycan requirement defined for IL-22 only"]},{"year":2006,"claim":"Defined the conformational basis of ternary complex assembly for IL-10, showing IL10RB docks only after IL-10R1 binding remodels helix A of the cytokine.","evidence":"SPR binding measurements with cell-based signaling, interpreted against IL-10/IL-10R1 crystal structures","pmids":["16982608"],"confidence":"High","gaps":["No direct structure of the IL10RB-bound ternary complex","Did not address whether the same conformational logic governs IFN-λ/IFN-υ complexes"]},{"year":2010,"claim":"Provided the structural explanation for IL10RB promiscuity by solving its ectodomain and identifying a conserved epitope flanked by two adaptable clefts.","evidence":"X-ray crystallography at 2.14 Å with alanine-scanning mutagenesis and computational docking of ternary complexes","pmids":["20462497"],"confidence":"High","gaps":["Ternary complexes were modeled computationally, not crystallized","Intracellular signaling consequences not addressed structurally"]},{"year":2017,"claim":"Dissected functional contributions of the IL10RB extracellular versus intracellular domains and linked the chain to Tyk2-controlled STAT3 amplitude.","evidence":"Bone marrow-derived cells from IL-10R-/- and Tyk2-/- mice with STAT3 phosphorylation, SOCS3 and LPS-induced TNF-α readouts","pmids":["29016674"],"confidence":"High","gaps":["Quantitative kinase-substrate relationship of Tyk2 to STAT3 not resolved","Mechanism by which intracellular domain alters IL-10R1 conformation unknown"]},{"year":2018,"claim":"Extended IL10RB function to antiviral IFN-λ4 signaling, showing the chain is required for type III interferon-mediated HIV restriction in macrophages.","evidence":"Antibody blockade of the IFN-λR1/IL-10R2 complex with STAT1 phosphorylation and ISG assays in HIV-infected macrophages","pmids":["30247785"],"confidence":"Medium","gaps":["Single lab, single method (antibody blockade)","Direct binding of IFN-λ4 to IL10RB not measured"]},{"year":2021,"claim":"Demonstrated causality and reversibility of IL10RB function in a human system by showing loss-of-function abolishes and gene correction restores the IL-10/STAT3/SOCS3 axis.","evidence":"Patient iPSC-derived macrophages with lentiviral gene therapy and AAVS1 genome editing; STAT3, SOCS3 and cytokine secretion readouts","pmids":["33804706"],"confidence":"High","gaps":["Did not test correction of other IL10RB-dependent cytokine systems","In vivo therapeutic durability not addressed"]},{"year":2022,"claim":"Identified IL10RB as the second chain for IFN-υ/type IV interferon, broadening its cytokine repertoire to a fifth receptor system.","evidence":"Chimeric receptor reconstitution in HEK293 cells with ISG and antiviral assays in zebrafish and Xenopus","pmids":["35194032"],"confidence":"High","gaps":["Human IFN-υ system not characterized","Structural basis of IFN-υR1/IL10RB complex unresolved"]},{"year":2024,"claim":"Revealed post-translational control of IL10RB surface availability through proteolytic cleavage by KLK2, defining a mechanism for dampening IL-10 signaling.","evidence":"FRET peptide library cleavage mapping (SYRIF 58-63), FACS of surface IL-10R2, and macrophage IL-10 functional assays with KLK3 negative control","pmids":["39106042"],"confidence":"Medium","gaps":["Physiological context of KLK2-mediated cleavage in vivo not established","Single lab"]},{"year":2024,"claim":"Implicated IL10RB in EMT-driven cancer cell properties and as a therapeutic antibody target, extending its role beyond canonical cytokine immunoregulation.","evidence":"Microarray, in vitro adhesion/invasion/chemoresistance assays, and mouse tumor models with anti-IL10RB blocking mAb and anti-PD1 combination","pmids":["41826681"],"confidence":"Medium","gaps":["Ligand/signaling pathway driving the cancer phenotype not defined","Single lab, mechanism downstream of IL10RB unclear"]},{"year":2025,"claim":"Placed IL10RB in a microglial-lifespan signaling axis acting through JAK/STAT and lysosomal pH regulation, a non-classical role in CNS cell death.","evidence":"CRISPR screen in zebrafish with confocal imaging, LysoTracker, JAK/STAT epistasis and v-ATPase inhibition (preprint)","pmids":["bio_10.1101_2025.11.21.689277"],"confidence":"Medium","gaps":["Preprint, single lab","Mechanistic link between IL10RB signaling and lysosomal acidification not resolved","Mammalian relevance untested"]},{"year":null,"claim":"How IL10RB selects among its many cytokine partners in vivo, and what governs the structure of the assembled, signaling-competent ternary complexes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental crystal/cryo-EM structure of any full ternary complex","Determinants of partner selectivity in cells expressing multiple R1 chains unknown","Human IFN-υ and CNS roles not validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,12]}],"complexes":["IL-10 receptor (IL-10R1/IL-10R2)","IL-22 receptor (IL-22R1/IL-10R2)","IFN-lambda receptor (IFN-lambdaR1/IL-10R2)","IFN-upsilon receptor (IFN-upsilonR1/IL-10R2)"],"partners":["IL10RA","IL22RA1","IFNLR1","TYK2","KLK2"],"other_free_text":[]}},"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":441,"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":331,"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 medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9463407","citation_count":296,"is_preprint":false},{"pmid":"15123776","id":"PMC_15123776","title":"The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain.","date":"2004","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/15123776","citation_count":234,"is_preprint":false},{"pmid":"16982608","id":"PMC_16982608","title":"Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16982608","citation_count":115,"is_preprint":false},{"pmid":"20462497","id":"PMC_20462497","title":"Structure and mechanism of receptor sharing by the IL-10R2 common chain.","date":"2010","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/20462497","citation_count":74,"is_preprint":false},{"pmid":"35194032","id":"PMC_35194032","title":"Identification and establishment of type IV interferon and the characterization of interferon-υ including its class II cytokine receptors IFN-υR1 and IL-10R2.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35194032","citation_count":72,"is_preprint":false},{"pmid":"15327950","id":"PMC_15327950","title":"The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix and is dependent on N-linked glycosylation.","date":"2004","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15327950","citation_count":62,"is_preprint":false},{"pmid":"15120653","id":"PMC_15120653","title":"Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2.","date":"2004","source":"International 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recombination gene knockout in mice; cytokine responsiveness assays; histopathological analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined cellular and systemic phenotype, mechanistically placing IL10RB as an obligate IL-10 receptor subunit; replicated conceptually by multiple subsequent studies\",\n      \"pmids\": [\"9463407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-22 signals through a receptor complex consisting of CRF2-4 (IL10RB) and a novel receptor chain (IL-22R/CRF2-9); CRF2-4 alone can bind IL-22 but both chains are required for functional signaling; IL-22 activates STATs 1, 3, and 5.\",\n      \"method\": \"Receptor expression in COS and hamster cells; STAT activation assays; radiolabeled cytokine cross-linking/binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent papers (PMID 10875937 and 11035029) using cell-based functional assays and direct binding studies establish IL10RB as a shared signaling subunit for IL-22\",\n      \"pmids\": [\"10875937\", \"11035029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL10RB (IL-10R2) is a shared common chain of both the IL-10 and IL-22 (IL-TIF) receptor complexes; each chain (CRF2-9 and IL-10R2) can independently bind IL-TIF, but binding affinity is greater when both chains form the complete receptor complex; the CRF2-9 chain is responsible for STAT recruitment.\",\n      \"method\": \"Receptor reconstitution in hamster and COS cells; radiolabeled cytokine cross-linking; STAT activation assays; intracellular domain substitution experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstitution in multiple cell lines, direct binding studies, domain-swap mutagenesis establishing distinct roles of each receptor chain\",\n      \"pmids\": [\"11035029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-10R2 (IL10RB) is a shared component of at least four distinct class II cytokine receptor complexes (IL-10, IL-22, IL-26, and IFN-lambda); neutralizing antibodies to the IL-10R2 chain block signaling by all four cytokines; IL-10R2 engagement occurs after the ligand binds its R1 chain, triggered by a conformational change.\",\n      \"method\": \"Neutralizing antibody blockade of cytokine signaling; receptor complex characterization; cell-based signaling assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blockade experiments across multiple cytokine systems, single review-style paper but with direct experimental support cited\",\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 (helix A) and requires N-linked glycosylation at asparagine 54; a single fucosylated N-acetyl glucosamine at N54 is required for maximal IL-10R2 binding, and IL-22 mutants with reduced IL-10R2 binding show correspondingly reduced biological activity.\",\n      \"method\": \"Surface plasmon resonance (SPR); site-directed mutagenesis; glycosylation characterization; cell-based luciferase reporter assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro SPR binding assays with mutagenesis and cell-based functional validation in a single rigorous study\",\n      \"pmids\": [\"15327950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-10R2 (IL10RB) binds to a surface created by the interaction between IL-22 and IL-22R, thereby further stabilizing the cytokine-receptor complex; IL-10R2 has undetectable affinity for IL-22 alone but substantially greater affinity for IL-22/IL-22R complexes.\",\n      \"method\": \"ELISA-based binding assays with biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments with receptor homodimers\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays with receptor fusion proteins establishing sequential assembly mechanism, single lab\",\n      \"pmids\": [\"15120653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Assembly of the IL-10 ternary signaling complex (IL-10/IL-10R1/IL-10R2) is sequential: IL-10 first binds IL-10R1, which induces conformational changes in helix A of IL-10 that create the IL-10R2 binding site; critical IL-10R2 binding residues are located in helix A adjacent to the IL-10R1 recognition surface.\",\n      \"method\": \"Surface plasmon resonance (SPR); cell-based signaling assays; comparison with IL-10/IL-10R1 crystal structures\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR binding measurements combined with structural analysis and cell-based validation, establishing conformational mechanism of sequential receptor assembly\",\n      \"pmids\": [\"16982608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IL-10R2 and IL-22R binding sites on IL-22 are topologically juxtaposed on adjacent and overlapping surfaces (helices A, D, F and loop AB); comprehensive mutagenesis identified amino acid residues individually important for IL-10R2 binding, considerably expanding the defined IL-10R2 binding surface on IL-22.\",\n      \"method\": \"Comprehensive site-directed mutagenesis; ELISA cell-based assays; structural modeling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive mutagenesis combined with cell-based binding assays and structural methods, single lab\",\n      \"pmids\": [\"18675824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The crystal structure of the IL-10R2 ectodomain at 2.14 Å resolution reveals a conserved binding epitope surrounded by two clefts that accommodate the structural and chemical diversity of different cytokine partners; alanine scanning identified IL-10R2 residues required for cytokine binding, and computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes were derived.\",\n      \"method\": \"X-ray crystallography at 2.14 Å; alanine scanning mutagenesis; computational docking/modeling\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination combined with functional mutagenesis providing structural mechanism of promiscuous receptor binding\",\n      \"pmids\": [\"20462497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Both the extracellular and intracellular domains of IL-10R2 (IL10RB) are required for transducing IL-10 signals; the intracellular domain of IL-10R2 influences the conformation of IL-10R1; IL-10-mediated responses depend on both IL-10R1 and IL-10R2 in dendritic cells, macrophages, and mast cells; IL-10R2-associated kinase Tyk2 controls the amplitude of STAT3 activation and SOCS3 upregulation but plays only a limited role in overall IL-10 responses.\",\n      \"method\": \"Bone marrow-derived cells from IL-10R-/- and Tyk2-/- mice; STAT3 phosphorylation assays; SOCS3 expression; LPS-induced TNF-α cytokine assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic knockouts with multiple orthogonal cellular readouts establishing distinct functional contributions of IL-10R2 extracellular and intracellular domains\",\n      \"pmids\": [\"29016674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Probiotic LGG upregulates IL-10R2 (IL10RB) subunit expression in developing murine colon, leading to enhanced IL-10 receptor-mediated signaling including increased STAT3 phosphorylation and SOCS3 expression; antibody-mediated blockade of the IL-10 receptor abrogated LGG-dependent reductions in TNF-α and MIP-2.\",\n      \"method\": \"Real-time PCR; STAT3 phosphorylation assays; antibody blockade of IL-10 receptor; murine model of intestinal injury\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with receptor blockade establishing functional link between IL-10R2 upregulation and downstream STAT3/SOCS3 signaling, single lab\",\n      \"pmids\": [\"23272193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function mutation in IL10RB abolishes IL-10-induced STAT3 phosphorylation and SOCS3 expression in iPSC-derived macrophages, preventing IL-10-mediated suppression of LPS-induced cytokine secretion (IL-6, TNF-α); lentiviral gene correction or genome editing of IL10RB reconstitutes IL-10-inducible STAT3 phosphorylation, SOCS3 expression, and anti-inflammatory regulation.\",\n      \"method\": \"iPSC differentiation into macrophages; STAT3 phosphorylation assays; SOCS3 expression; cytokine secretion assays; lentiviral gene therapy and AAVS1 safe harbor genome editing\",\n      \"journal\": \"Journal of personalized medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function (gene correction) in patient-derived iPSC-derived macrophages with multiple orthogonal functional readouts establishing causal role of IL10RB in IL-10/STAT3/SOCS3 signaling axis\",\n      \"pmids\": [\"33804706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFN-λ4 inhibits HIV infection of macrophages through signaling of the IFN-λR1/IL-10R2 receptor complex; antibodies against IFN-λR1/IL-10R2 compromise IFN-λ4-mediated HIV inhibition; IFN-λ4 enhances STAT1 phosphorylation and induces antiviral interferon-stimulated genes through this receptor complex.\",\n      \"method\": \"Antibody blockade of receptor complex; STAT1 phosphorylation assays; antiviral gene expression assays; HIV infection of macrophages\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — antibody blockade establishing IL-10R2 requirement for IFN-λ4 antiviral signaling, single lab, single method per finding\",\n      \"pmids\": [\"30247785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL10RB is identified as a receptor subunit for IFN-υ (type IV interferon) together with IFN-υR1; IFN-υR1/IL-10R2 receptor complex mediates IFN-υ-stimulated gene expression and antiviral activity in zebrafish and Xenopus; the receptor of IFN-υ was verified as IFN-υR1 and IL-10R2 using a chimeric receptor approach.\",\n      \"method\": \"Chimeric receptor approach in HEK293 cells; ISG expression assays; antiviral activity assays in zebrafish and Xenopus laevis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — chimeric receptor functional reconstitution combined with in vivo antiviral assays in two vertebrate models establishing IL10RB as receptor subunit for type IV IFN\",\n      \"pmids\": [\"35194032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The extracellular domain of IL-10R2 (IL10RB) is a substrate for KLK2 (prostate kallikrein-2), which cleaves the sequence SYRIF at positions 58-63 of IL-10R2; KLK2 treatment reduces surface IL-10R2 expression on bone marrow-derived macrophages and significantly reduces IL-10-mediated inhibition of inflammatory responses (nitric oxide, TNF-α, IL-12 p40) to LPS/IFN-γ.\",\n      \"method\": \"Fluorescence resonance energy transfer peptide library assays; flow cytometry (FACS) of cell surface IL-10R2; in vitro macrophage stimulation with LPS/IFN-γ and IL-10; comparison with KLK3 (negative control)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic cleavage assay with functional consequence on IL-10 signaling in primary macrophages, single lab with negative control\",\n      \"pmids\": [\"39106042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"il10rb perturbation in zebrafish reduces microglial death and decreases lysosomal acidification (reduced LysoTracker-positive lysosomes) without altering lysosome number or size, placing IL10RB in a signaling axis that controls microglial lifespan through lysosomal pH regulation; perturbation of il10, il10rb, and downstream JAK/STAT molecules all reduced microglial death.\",\n      \"method\": \"CRISPR screen in zebrafish using robotic confocal microscope; LysoTracker live imaging; genetic epistasis with JAK/STAT pathway genes; v-ATPase inhibition experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-based genetic screen with in vivo imaging and lysosomal functional readouts; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689277\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL10RB overexpression in cancer cells undergoing EMT (driven by snail) enhances cellular adhesion, invasiveness, and chemoresistance; anti-IL10RB blocking monoclonal antibody attenuates these refractory properties and induces anti-tumor immunity in mouse tumor models; combining anti-IL10RB and anti-PD1 therapy has synergistic effects on tumor disappearance.\",\n      \"method\": \"GeneChip microarray; in vitro adhesion, invasion, and chemoresistance assays in cancer cells; mouse orthotopic tumor models; anti-IL10RB blocking mAb treatment\",\n      \"journal\": \"BJC reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro functional assays and mouse tumor model with blocking antibody establishing IL10RB role in EMT-driven cancer cell properties, single lab\",\n      \"pmids\": [\"41826681\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL10RB (CRF2-4/IL-10R2) is a broadly expressed, obligate shared signaling subunit of at least five class II cytokine receptor complexes (for IL-10, IL-22, IL-26, IFN-λ, and IFN-υ/type IV IFN); it engages these complexes secondarily after each ligand binds its primary R1 receptor chain (a conformational change-dependent step), contributes both extracellular and intracellular domains to receptor activation, associates intracellularly with Tyk2 to modulate STAT3 amplitude, and is required for IL-10-induced STAT3 phosphorylation and SOCS3 upregulation that underlies IL-10's anti-inflammatory actions; its crystal structure reveals a conserved but adaptable binding epitope accommodating diverse cytokine partners through two flanking clefts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL10RB (CRF2-4/IL-10R2) is an obligate, broadly shared signaling subunit of multiple class II cytokine receptor complexes, required to transduce the anti-inflammatory and antiviral programs of its cytokine partners [#0, #3]. Genetic disruption abolishes IL-10 responsiveness while sparing type I and type II interferon signaling, and produces chronic colitis recapitulating IL-10 deficiency, establishing IL10RB as non-redundant in the IL-10 axis [#0]. Beyond IL-10 it serves as the common second chain partnering distinct primary R1 receptors for IL-22, IL-26, IFN-\\u03bb, and the IFN-\\u03c5/type IV IFN system, and neutralizing the IL-10R2 chain blocks signaling by all of these cytokines [#1, #2, #3, #12, #13]. Receptor assembly is sequential and conformation-dependent: IL10RB has negligible affinity for free cytokine and instead docks onto a composite surface formed only after the ligand engages its R1 chain, which remodels the cytokine (notably helix A of IL-10 and IL-22) to create the IL-10R2 epitope [#5, #6]. Its crystal structure reveals a conserved binding epitope flanked by two clefts that accommodate the chemical and structural diversity of its many cytokine partners [#8]. Both the extracellular and intracellular domains of IL-10R2 are required for signal transduction; the intracellular domain shapes IL-10R1 conformation and the IL-10R2-associated kinase Tyk2 controls the amplitude of STAT3 phosphorylation and SOCS3 upregulation, the core node of IL-10's anti-inflammatory output [#9]. Loss-of-function mutation in IL10RB abolishes IL-10-induced STAT3 phosphorylation and SOCS3 expression in human macrophages, and gene correction restores anti-inflammatory regulation, demonstrating a causal requirement for IL10RB in this axis [#11]. Surface availability of IL-10R2 is post-translationally regulated: the protease KLK2 cleaves the IL-10R2 ectodomain (SYRIF, residues 58\\u201363), reducing surface receptor and dampening IL-10 signaling [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that IL10RB is a non-redundant subunit of the IL-10 receptor, answering whether this orphan class II chain has a defined ligand system and physiological role.\",\n      \"evidence\": \"Homozygous CRFB4 gene knockout in mice with cytokine responsiveness and histopathology\",\n      \"pmids\": [\"9463407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular partner chain (IL-10R1) interaction mechanism\", \"Did not address whether the chain is shared by other cytokines\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that IL10RB is a shared chain serving IL-22 in addition to IL-10, reframing it as a common signaling subunit rather than an IL-10-specific receptor.\",\n      \"evidence\": \"Receptor reconstitution in COS/hamster cells, radiolabeled cytokine cross-linking, STAT activation and intracellular-domain swap assays\",\n      \"pmids\": [\"10875937\", \"11035029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the order of chain assembly\", \"Did not resolve which residues mediate IL10RB binding\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the shared-chain model to four cytokine systems and introduced the sequential, conformation-triggered assembly mechanism, answering how one chain can serve diverse ligands.\",\n      \"evidence\": \"Neutralizing antibody blockade across IL-10, IL-22, IL-26 and IFN-\\u03bb signaling; ELISA and SPR binding with mutagenesis on IL-22\",\n      \"pmids\": [\"15123776\", \"15327950\", \"15120653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Assembly mechanism inferred from binding kinetics rather than direct structure\", \"Glycan requirement defined for IL-22 only\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the conformational basis of ternary complex assembly for IL-10, showing IL10RB docks only after IL-10R1 binding remodels helix A of the cytokine.\",\n      \"evidence\": \"SPR binding measurements with cell-based signaling, interpreted against IL-10/IL-10R1 crystal structures\",\n      \"pmids\": [\"16982608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct structure of the IL10RB-bound ternary complex\", \"Did not address whether the same conformational logic governs IFN-\\u03bb/IFN-\\u03c5 complexes\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural explanation for IL10RB promiscuity by solving its ectodomain and identifying a conserved epitope flanked by two adaptable clefts.\",\n      \"evidence\": \"X-ray crystallography at 2.14 \\u00c5 with alanine-scanning mutagenesis and computational docking of ternary complexes\",\n      \"pmids\": [\"20462497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ternary complexes were modeled computationally, not crystallized\", \"Intracellular signaling consequences not addressed structurally\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected functional contributions of the IL10RB extracellular versus intracellular domains and linked the chain to Tyk2-controlled STAT3 amplitude.\",\n      \"evidence\": \"Bone marrow-derived cells from IL-10R-/- and Tyk2-/- mice with STAT3 phosphorylation, SOCS3 and LPS-induced TNF-\\u03b1 readouts\",\n      \"pmids\": [\"29016674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative kinase-substrate relationship of Tyk2 to STAT3 not resolved\", \"Mechanism by which intracellular domain alters IL-10R1 conformation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended IL10RB function to antiviral IFN-\\u03bb4 signaling, showing the chain is required for type III interferon-mediated HIV restriction in macrophages.\",\n      \"evidence\": \"Antibody blockade of the IFN-\\u03bbR1/IL-10R2 complex with STAT1 phosphorylation and ISG assays in HIV-infected macrophages\",\n      \"pmids\": [\"30247785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single method (antibody blockade)\", \"Direct binding of IFN-\\u03bb4 to IL10RB not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated causality and reversibility of IL10RB function in a human system by showing loss-of-function abolishes and gene correction restores the IL-10/STAT3/SOCS3 axis.\",\n      \"evidence\": \"Patient iPSC-derived macrophages with lentiviral gene therapy and AAVS1 genome editing; STAT3, SOCS3 and cytokine secretion readouts\",\n      \"pmids\": [\"33804706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test correction of other IL10RB-dependent cytokine systems\", \"In vivo therapeutic durability not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified IL10RB as the second chain for IFN-\\u03c5/type IV interferon, broadening its cytokine repertoire to a fifth receptor system.\",\n      \"evidence\": \"Chimeric receptor reconstitution in HEK293 cells with ISG and antiviral assays in zebrafish and Xenopus\",\n      \"pmids\": [\"35194032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human IFN-\\u03c5 system not characterized\", \"Structural basis of IFN-\\u03c5R1/IL10RB complex unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed post-translational control of IL10RB surface availability through proteolytic cleavage by KLK2, defining a mechanism for dampening IL-10 signaling.\",\n      \"evidence\": \"FRET peptide library cleavage mapping (SYRIF 58-63), FACS of surface IL-10R2, and macrophage IL-10 functional assays with KLK3 negative control\",\n      \"pmids\": [\"39106042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of KLK2-mediated cleavage in vivo not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated IL10RB in EMT-driven cancer cell properties and as a therapeutic antibody target, extending its role beyond canonical cytokine immunoregulation.\",\n      \"evidence\": \"Microarray, in vitro adhesion/invasion/chemoresistance assays, and mouse tumor models with anti-IL10RB blocking mAb and anti-PD1 combination\",\n      \"pmids\": [\"41826681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand/signaling pathway driving the cancer phenotype not defined\", \"Single lab, mechanism downstream of IL10RB unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed IL10RB in a microglial-lifespan signaling axis acting through JAK/STAT and lysosomal pH regulation, a non-classical role in CNS cell death.\",\n      \"evidence\": \"CRISPR screen in zebrafish with confocal imaging, LysoTracker, JAK/STAT epistasis and v-ATPase inhibition (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Mechanistic link between IL10RB signaling and lysosomal acidification not resolved\", \"Mammalian relevance untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL10RB selects among its many cytokine partners in vivo, and what governs the structure of the assembled, signaling-competent ternary complexes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental crystal/cryo-EM structure of any full ternary complex\", \"Determinants of partner selectivity in cells expressing multiple R1 chains unknown\", \"Human IFN-\\u03c5 and CNS roles not validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0004888\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 12]}\n    ],\n    \"complexes\": [\n      \"IL-10 receptor (IL-10R1/IL-10R2)\",\n      \"IL-22 receptor (IL-22R1/IL-10R2)\",\n      \"IFN-lambda receptor (IFN-lambdaR1/IL-10R2)\",\n      \"IFN-upsilon receptor (IFN-upsilonR1/IL-10R2)\"\n    ],\n    \"partners\": [\n      \"IL10RA\",\n      \"IL22RA1\",\n      \"IFNLR1\",\n      \"TYK2\",\n      \"KLK2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}