{"gene":"IL20RB","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IL-20RB (IL-20R2) is a shared subunit of two heterodimeric receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2, both of which serve as functional receptors for IL-24. COS cells transfected with either heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to either receptor complex activates STAT transcription factors.","method":"Receptor binding assays in transfected COS cells, STAT activation assays in keratinocytes and BHK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays with multiple cell types and downstream signaling readout; replicated across subsequent structural studies","pmids":["11706020"],"is_preprint":false},{"year":2006,"finding":"IL-20R2 (IL-20RB) is required for IL-23-dependent epidermal hyperplasia in mouse skin. IL-23 induces IL-19 and IL-24 expression, and whereas IL-19-/- and IL-24-/- mice still develop epidermal hyperplasia, IL-20R2-/- mice are protected, placing IL-20R2 downstream of IL-23 in this inflammatory cascade.","method":"Genetic epistasis using IL-20R2-/- knockout mice with intradermal IL-23 injection and histological readout","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse model with defined phenotypic readout, replicated across multiple cytokine knockout comparisons in same study","pmids":["17074928"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex reveals how type I (IL-20R1/IL-20R2) and type II (IL-22R1/IL-20R2) receptor complexes discriminate cognate from noncognate ligands, and how receptor-cytokine interfaces are affinity-tuned to allow distinct signaling through the shared IL-20R2 subunit by three different ligands (IL-19, IL-20, IL-24).","method":"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional interpretation; provides atomic-level basis for receptor sharing and ligand discrimination","pmids":["22802649"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of the IL-24/IL-22R1/IL-20R2 ternary complex at 2.15 Å resolution shows that two cysteine residues in IL-24 do not form a predicted disulfide bond (unlike related cytokines), explaining IL-24 instability; calculations indicate the IL-24–IL-20R2 interaction is slightly more stable than IL-24–IL-22R1, suggesting IL-20R2 is the higher-affinity receptor in the type II complex.","method":"X-ray crystallography of the IL-24/IL-22R1/IL-20R2 ternary complex at 2.15 Å; cell-based signaling assays with refolded IL-24","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure with computational stability calculations and functional cell-based validation; single lab","pmids":["30111632"],"is_preprint":false},{"year":2016,"finding":"Alternative splicing of IL-20R2 (IL-20RB) produces a second isoform that survives exon I ablation, explaining why IL-20R2 exon I knockout mice do not fully recapitulate expected loss-of-function psoriatic phenotypes. The surviving isoform retains functional receptor activity.","method":"Molecular cloning of alternatively spliced transcript, PCR sequencing, imiquimod-induced psoriasis mouse model","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of a novel isoform by molecular biology with in vivo functional implication; single lab","pmids":["27009487"],"is_preprint":false},{"year":2020,"finding":"Toxoplasma gondii rhoptry protein TgROP18 physically interacts with the extracellular domain of IL-20RB on host cells and activates the host JAK/STAT3 pathway. STAT3 phosphorylation by recombinant TgROP18 is dose-dependent and occurs only in cells with endogenous IL-20RB expression, demonstrating that TgROP18 hijacks the IL-20RB signaling axis to activate host immune responses including TNF-α expression.","method":"Co-immunoprecipitation, FRET, CRISPR-Cas9 double knockout of TgROP16/TgROP18, recombinant protein treatment of cell lines with differential IL-20RB expression, western blot for phospho-STAT3","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and FRET for interaction, functional validation with dose-response and cell lines differing in endogenous IL-20RB; single lab","pmids":["32767999"],"is_preprint":false},{"year":2022,"finding":"IL-20RB mediates a direct pro-tumoral response to osteoclasts in bone metastasis of lung cancer. Tumor cells induce osteoclasts to secrete IL-19, which signals through IL-20RB on tumor cells to activate JAK1/STAT3 signaling, enhancing tumor cell proliferation in bone. Blocking IL-20RB with a neutralizing antibody suppresses bone metastasis in vivo.","method":"IL-20RB overexpression/knockdown in lung cancer cell lines, in vivo bone metastasis models, neutralizing antibody treatment, western blot for JAK1/STAT3 phosphorylation","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined signaling readout and in vivo validation; single lab","pmids":["36006737"],"is_preprint":false},{"year":2023,"finding":"IL-20RB promotes stemness and chemoresistance in pancreatic cancer via STAT3 phosphorylation. IL-19 from the tumor microenvironment is the primary ligand mediating these effects. STAT3 phosphorylation inhibitors counteract IL-20RB-driven stemness and chemoresistance.","method":"IL-20RB overexpression and knockdown in pancreatic cancer cell lines, clonal/spheroid formation and side-population analysis in vitro, in vivo tumor formation and chemotherapy resistance models, pharmacological inhibition of STAT3","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal cellular assays and in vivo validation; single lab","pmids":["38098005"],"is_preprint":false},{"year":2024,"finding":"IL-20RB promotes pulmonary fibrosis by enhancing the activation of bone marrow-derived pro-fibrotic macrophages. Mechanistically, IL-20RB regulates Jak2/STAT3 and PI3K/Akt signaling pathways in macrophages. Absence of IL-20RB alleviates bleomycin-induced fibrosis, and neutralizing antibodies against IL-20RB reduce IPF progression in animal models.","method":"Bleomycin-induced pulmonary fibrosis mouse model, IL4/13-induced THP1 macrophage polarization, IL-20RB knockout and neutralizing antibody treatment, western blot for JAK2/STAT3 and PI3K/Akt phosphorylation","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model and cell-based mechanistic assays with in vivo therapeutic validation; single lab","pmids":["38583686"],"is_preprint":false},{"year":2023,"finding":"Photocaged non-canonical amino acid (ortho-nitrobenzyl-tyrosine) introduced at tyrosine70 of IL-20R2 impairs IL-24/IL-20R2 heterocomplex assembly in the dark; UV irradiation at 365 nm decages the residue, reconstituting native tyrosine and restoring IL-24 binding and downstream JAK/STAT phosphorylation. This identifies tyrosine70 of IL-20R2 as a functionally critical residue at the IL-24/IL-20R2 interface.","method":"Genetic code expansion with photocaged non-canonical amino acids, biophysical binding assays, cell signaling assays for JAK/STAT phosphorylation","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — site-specific mutagenesis equivalent (photocaged amino acid) with functional signaling readout; single lab, single study","pmids":["37484532"],"is_preprint":false},{"year":2025,"finding":"The E3 ubiquitin ligase TRIM21 promotes ubiquitin-dependent degradation of TAp63α, which normally transcriptionally represses IL-20RB by inducing promoter methylation. Loss of TAp63α derepresses IL-20RB, increasing IL-20 receptor formation and activating downstream JAK1-STAT3 signaling to drive PDAC proliferation, EMT, migration, and in vivo metastatic seeding.","method":"TAp63α overexpression/knockdown in PDAC cell lines, TRIM21 manipulation, ubiquitination assays, promoter methylation analysis, JAK1-STAT3 western blot, in vivo metastasis model","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ubiquitination, promoter methylation, signaling assays, in vivo model) in a single lab study establishing a regulatory axis upstream of IL-20RB","pmids":["40460193"],"is_preprint":false},{"year":2019,"finding":"Knockdown of IL-20R2 (IL-20RB) in mice reduces psoriasis-like pathological changes induced by imiquimod, confirmed by reduced IL-20R2 protein and mRNA in skin tissue.","method":"IL-20R2 knockdown mice, imiquimod-induced psoriasis model, HE staining, western blot, PCR","journal":"Xi bao yu fen zi mian yi xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, loss-of-function phenotype without detailed pathway placement; partial knockdown rather than full KO","pmids":["31167692"],"is_preprint":false}],"current_model":"IL-20RB (IL-20R2) is a shared receptor subunit that heterodimerizes with either IL-20R1 or IL-22R1 to form two distinct receptor complexes that bind IL-19, IL-20, and/or IL-24, with structural studies defining the affinity-tuned cytokine-receptor interfaces; ligand engagement activates downstream JAK/STAT3 (and PI3K/Akt) signaling, mediating roles in epidermal homeostasis, psoriasis, pulmonary fibrosis, and cancer progression, while upstream regulation includes transcriptional repression by TAp63α (relieved by TRIM21-mediated degradation) and a functionally critical tyrosine70 residue at the IL-24 binding interface."},"narrative":{"mechanistic_narrative":"IL20RB (IL-20R2) is a shared receptor subunit that pairs with either IL-20R1 or IL-22R1 to assemble two distinct heterodimeric receptor complexes, both of which bind IL-24 and signal through STAT transcription factors [PMID:11706020]. Crystal structures of the IL-20/IL-20R1/IL-20R2 and IL-24/IL-22R1/IL-20R2 ternary complexes define how affinity-tuned cytokine–receptor interfaces allow the single shared IL-20R2 subunit to discriminate among IL-19, IL-20, and IL-24, with IL-20R2 contributing the higher-affinity contact in the type II complex [PMID:22802649, PMID:30111632]; tyrosine70 of IL-20R2 is a functionally critical residue at the IL-24/IL-20R2 interface required for heterocomplex assembly and downstream JAK/STAT activation [PMID:37484532]. Ligand engagement of IL-20RB activates JAK/STAT3 — and in some contexts PI3K/Akt — signaling, a circuit that places the receptor downstream of IL-23 in epidermal hyperplasia and psoriasis-like skin inflammation in mice [PMID:17074928] and that drives pro-fibrotic macrophage activation in bleomycin-induced pulmonary fibrosis [PMID:38583686]. The same IL-19/IL-20RB/JAK1-STAT3 axis is co-opted in cancer, where it promotes osteoclast-driven bone metastasis of lung cancer [PMID:36006737] and stemness, chemoresistance, and metastatic seeding in pancreatic ductal adenocarcinoma [PMID:38098005, PMID:40460193]; receptor expression is held in check by TAp63α-mediated promoter methylation, which is relieved when TRIM21 degrades TAp63α [PMID:40460193]. Beyond its cytokine-receptor role, the Toxoplasma gondii rhoptry protein TgROP18 binds the IL-20RB extracellular domain to hijack host JAK/STAT3 signaling [PMID:32767999].","teleology":[{"year":2001,"claim":"Established that IL-20RB is not a standalone receptor but a shared subunit of two heterodimeric complexes, resolving how a single chain serves multiple cytokines.","evidence":"Receptor binding assays in transfected COS cells with STAT activation readout in keratinocytes and BHK cells","pmids":["11706020"],"confidence":"High","gaps":["Did not define the atomic interfaces distinguishing the two complexes","Did not assign ligand-specific affinities among IL-19/IL-20/IL-24"]},{"year":2006,"claim":"Placed IL-20RB downstream of IL-23 in an inflammatory cascade, defining its role in epidermal hyperplasia genetically rather than by association.","evidence":"Genetic epistasis with IL-20R2-/- knockout mice, intradermal IL-23 injection, histology","pmids":["17074928"],"confidence":"High","gaps":["Which ligand(s) acting through IL-20RB drive the phenotype was not pinpointed","Downstream signaling in skin not dissected"]},{"year":2012,"claim":"Provided the atomic basis for how the shared IL-20R2 subunit discriminates cognate from noncognate ligands across type I and type II complexes.","evidence":"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 ternary complex","pmids":["22802649"],"confidence":"High","gaps":["Static structure does not capture assembly kinetics","Signaling-competent versus non-productive complex states not resolved"]},{"year":2016,"claim":"Explained discrepant knockout phenotypes by identifying an alternatively spliced IL-20RB isoform that survives exon I ablation and retains receptor function.","evidence":"Molecular cloning, PCR sequencing, imiquimod psoriasis mouse model","pmids":["27009487"],"confidence":"Medium","gaps":["Relative abundance and tissue distribution of the isoform not quantified","Whether isoforms differ in ligand affinity not tested"]},{"year":2018,"claim":"Refined the type II complex interface, showing a missing disulfide explains IL-24 instability and that IL-20RB is the higher-affinity receptor for IL-24.","evidence":"X-ray crystallography of IL-24/IL-22R1/IL-20R2 at 2.15 Å with cell-based signaling using refolded IL-24","pmids":["30111632"],"confidence":"High","gaps":["Affinity ranking rests partly on computational calculation","Single lab structure"]},{"year":2019,"claim":"Reinforced the requirement for IL-20RB in psoriasis-like skin pathology via knockdown.","evidence":"IL-20R2 knockdown mice, imiquimod psoriasis model, histology, western blot, PCR","pmids":["31167692"],"confidence":"Low","gaps":["Partial knockdown rather than full knockout","No detailed pathway placement","Single lab"]},{"year":2020,"claim":"Revealed that a pathogen virulence factor can engage the IL-20RB extracellular domain to commandeer host JAK/STAT3 signaling, extending the receptor's biology beyond cognate cytokines.","evidence":"Co-IP, FRET, CRISPR double knockout, recombinant TgROP18 on cell lines with differential IL-20RB expression, phospho-STAT3 western blot","pmids":["32767999"],"confidence":"Medium","gaps":["Physiological relevance during infection not established","Binding site on IL-20RB not mapped","Single lab"]},{"year":2022,"claim":"Defined an IL-19/IL-20RB/JAK1-STAT3 paracrine axis driving osteoclast-mediated bone metastasis, and showed therapeutic tractability via antibody blockade.","evidence":"Gain/loss-of-function in lung cancer lines, in vivo bone metastasis models, neutralizing antibody, JAK1/STAT3 phospho-western blot","pmids":["36006737"],"confidence":"Medium","gaps":["Generalizability beyond bone microenvironment unclear","Single lab"]},{"year":2023,"claim":"Extended the IL-19/IL-20RB/STAT3 axis to pancreatic cancer stemness and chemoresistance, identifying STAT3 phosphorylation as the actionable node.","evidence":"Gain/loss-of-function in PDAC lines, spheroid and side-population assays, in vivo tumor and chemoresistance models, STAT3 inhibition","pmids":["38098005"],"confidence":"Medium","gaps":["Contribution of other ligands not excluded","Single lab"]},{"year":2023,"claim":"Identified tyrosine70 of IL-20RB as a functionally critical interface residue using a photocaged amino acid as a reversible switch for complex assembly.","evidence":"Genetic code expansion with photocaged ortho-nitrobenzyl-tyrosine, biophysical binding and JAK/STAT signaling assays","pmids":["37484532"],"confidence":"Medium","gaps":["Single residue tested in isolation","Single lab, single study"]},{"year":2025,"claim":"Established the upstream transcriptional control of IL-20RB, showing TRIM21-driven degradation of TAp63α derepresses the IL-20RB promoter to fuel PDAC progression.","evidence":"TAp63α and TRIM21 manipulation in PDAC lines, ubiquitination assays, promoter methylation analysis, JAK1-STAT3 western blot, in vivo metastasis model","pmids":["40460193"],"confidence":"Medium","gaps":["Direct TAp63α occupancy at the promoter versus indirect effects not fully separated","Single lab"]},{"year":null,"claim":"How ligand-specific IL-20RB signaling outputs are differentially decoded across tissues (skin, lung, bone, pancreas) and whether the two complexes route to distinct downstream programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified comparison of type I versus type II signaling outputs","Ligand-specific transcriptional programs not mapped","Endogenous IL-20RB structural state in signaling-competent membranes not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,10]}],"complexes":["IL-20R1/IL-20R2 (type I) receptor","IL-22R1/IL-20R2 (type II) receptor"],"partners":["IL20RA","IL22RA1","IL24","IL20","IL19","TGROP18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXL0","full_name":"Interleukin-20 receptor subunit beta","aliases":["Fibronectin type III domain containing 6","FNDC6","IL-20R2"],"length_aa":311,"mass_kda":35.1,"function":"The IL20RA/IL20RB dimer is a receptor for IL19, IL20 and IL24. The IL22RA1/IL20RB dimer is a receptor for IL20 and IL24","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q6UXL0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL20RB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL20RB","total_profiled":1310},"omim":[{"mim_id":"605621","title":"INTERLEUKIN 20 RECEPTOR, BETA; IL20RB","url":"https://www.omim.org/entry/605621"},{"mim_id":"605620","title":"INTERLEUKIN 20 RECEPTOR, ALPHA; IL20RA","url":"https://www.omim.org/entry/605620"},{"mim_id":"605619","title":"INTERLEUKIN 20; IL20","url":"https://www.omim.org/entry/605619"},{"mim_id":"605457","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-1; IL22RA1","url":"https://www.omim.org/entry/605457"},{"mim_id":"605330","title":"INTERLEUKIN 22; IL22","url":"https://www.omim.org/entry/605330"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":58.4},{"tissue":"esophagus","ntpm":121.1},{"tissue":"skin 1","ntpm":165.8},{"tissue":"vagina","ntpm":74.4}],"url":"https://www.proteinatlas.org/search/IL20RB"},"hgnc":{"alias_symbol":["DIRS1","IL-20R2","MGC34923"],"prev_symbol":["FNDC6"]},"alphafold":{"accession":"Q6UXL0","domains":[{"cath_id":"2.60.40.10","chopping":"40-136","consensus_level":"high","plddt":95.5273,"start":40,"end":136},{"cath_id":"2.60.40.10","chopping":"144-227","consensus_level":"high","plddt":95.0924,"start":144,"end":227}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXL0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXL0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXL0-F1-predicted_aligned_error_v6.png","plddt_mean":83.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL20RB","jax_strain_url":"https://www.jax.org/strain/search?query=IL20RB"},"sequence":{"accession":"Q6UXL0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXL0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXL0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXL0"}},"corpus_meta":[{"pmid":"17074928","id":"PMC_17074928","title":"IL-23 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31167692","citation_count":1,"is_preprint":false},{"pmid":"22232181","id":"PMC_22232181","title":"Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex.","date":"2011","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22232181","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.10.642348","title":"Fluorescein Angiography Image-AI Based Early Diabetic Retinopathy Detection","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.10.642348","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.12.648530","title":"Retroelement expansions underlie genome evolution in stingless bees","date":"2025-04-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.12.648530","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15528,"output_tokens":3308,"usd":0.048102,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10818,"output_tokens":3577,"usd":0.071758,"stage2_stop_reason":"end_turn"},"total_usd":0.11986,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-20RB (IL-20R2) is a shared subunit of two heterodimeric receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2, both of which serve as functional receptors for IL-24. COS cells transfected with either heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to either receptor complex activates STAT transcription factors.\",\n      \"method\": \"Receptor binding assays in transfected COS cells, STAT activation assays in keratinocytes and BHK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays with multiple cell types and downstream signaling readout; replicated across subsequent structural studies\",\n      \"pmids\": [\"11706020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-20R2 (IL-20RB) is required for IL-23-dependent epidermal hyperplasia in mouse skin. IL-23 induces IL-19 and IL-24 expression, and whereas IL-19-/- and IL-24-/- mice still develop epidermal hyperplasia, IL-20R2-/- mice are protected, placing IL-20R2 downstream of IL-23 in this inflammatory cascade.\",\n      \"method\": \"Genetic epistasis using IL-20R2-/- knockout mice with intradermal IL-23 injection and histological readout\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse model with defined phenotypic readout, replicated across multiple cytokine knockout comparisons in same study\",\n      \"pmids\": [\"17074928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex reveals how type I (IL-20R1/IL-20R2) and type II (IL-22R1/IL-20R2) receptor complexes discriminate cognate from noncognate ligands, and how receptor-cytokine interfaces are affinity-tuned to allow distinct signaling through the shared IL-20R2 subunit by three different ligands (IL-19, IL-20, IL-24).\",\n      \"method\": \"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional interpretation; provides atomic-level basis for receptor sharing and ligand discrimination\",\n      \"pmids\": [\"22802649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of the IL-24/IL-22R1/IL-20R2 ternary complex at 2.15 Å resolution shows that two cysteine residues in IL-24 do not form a predicted disulfide bond (unlike related cytokines), explaining IL-24 instability; calculations indicate the IL-24–IL-20R2 interaction is slightly more stable than IL-24–IL-22R1, suggesting IL-20R2 is the higher-affinity receptor in the type II complex.\",\n      \"method\": \"X-ray crystallography of the IL-24/IL-22R1/IL-20R2 ternary complex at 2.15 Å; cell-based signaling assays with refolded IL-24\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure with computational stability calculations and functional cell-based validation; single lab\",\n      \"pmids\": [\"30111632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Alternative splicing of IL-20R2 (IL-20RB) produces a second isoform that survives exon I ablation, explaining why IL-20R2 exon I knockout mice do not fully recapitulate expected loss-of-function psoriatic phenotypes. The surviving isoform retains functional receptor activity.\",\n      \"method\": \"Molecular cloning of alternatively spliced transcript, PCR sequencing, imiquimod-induced psoriasis mouse model\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of a novel isoform by molecular biology with in vivo functional implication; single lab\",\n      \"pmids\": [\"27009487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Toxoplasma gondii rhoptry protein TgROP18 physically interacts with the extracellular domain of IL-20RB on host cells and activates the host JAK/STAT3 pathway. STAT3 phosphorylation by recombinant TgROP18 is dose-dependent and occurs only in cells with endogenous IL-20RB expression, demonstrating that TgROP18 hijacks the IL-20RB signaling axis to activate host immune responses including TNF-α expression.\",\n      \"method\": \"Co-immunoprecipitation, FRET, CRISPR-Cas9 double knockout of TgROP16/TgROP18, recombinant protein treatment of cell lines with differential IL-20RB expression, western blot for phospho-STAT3\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and FRET for interaction, functional validation with dose-response and cell lines differing in endogenous IL-20RB; single lab\",\n      \"pmids\": [\"32767999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-20RB mediates a direct pro-tumoral response to osteoclasts in bone metastasis of lung cancer. Tumor cells induce osteoclasts to secrete IL-19, which signals through IL-20RB on tumor cells to activate JAK1/STAT3 signaling, enhancing tumor cell proliferation in bone. Blocking IL-20RB with a neutralizing antibody suppresses bone metastasis in vivo.\",\n      \"method\": \"IL-20RB overexpression/knockdown in lung cancer cell lines, in vivo bone metastasis models, neutralizing antibody treatment, western blot for JAK1/STAT3 phosphorylation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined signaling readout and in vivo validation; single lab\",\n      \"pmids\": [\"36006737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-20RB promotes stemness and chemoresistance in pancreatic cancer via STAT3 phosphorylation. IL-19 from the tumor microenvironment is the primary ligand mediating these effects. STAT3 phosphorylation inhibitors counteract IL-20RB-driven stemness and chemoresistance.\",\n      \"method\": \"IL-20RB overexpression and knockdown in pancreatic cancer cell lines, clonal/spheroid formation and side-population analysis in vitro, in vivo tumor formation and chemotherapy resistance models, pharmacological inhibition of STAT3\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal cellular assays and in vivo validation; single lab\",\n      \"pmids\": [\"38098005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-20RB promotes pulmonary fibrosis by enhancing the activation of bone marrow-derived pro-fibrotic macrophages. Mechanistically, IL-20RB regulates Jak2/STAT3 and PI3K/Akt signaling pathways in macrophages. Absence of IL-20RB alleviates bleomycin-induced fibrosis, and neutralizing antibodies against IL-20RB reduce IPF progression in animal models.\",\n      \"method\": \"Bleomycin-induced pulmonary fibrosis mouse model, IL4/13-induced THP1 macrophage polarization, IL-20RB knockout and neutralizing antibody treatment, western blot for JAK2/STAT3 and PI3K/Akt phosphorylation\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model and cell-based mechanistic assays with in vivo therapeutic validation; single lab\",\n      \"pmids\": [\"38583686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Photocaged non-canonical amino acid (ortho-nitrobenzyl-tyrosine) introduced at tyrosine70 of IL-20R2 impairs IL-24/IL-20R2 heterocomplex assembly in the dark; UV irradiation at 365 nm decages the residue, reconstituting native tyrosine and restoring IL-24 binding and downstream JAK/STAT phosphorylation. This identifies tyrosine70 of IL-20R2 as a functionally critical residue at the IL-24/IL-20R2 interface.\",\n      \"method\": \"Genetic code expansion with photocaged non-canonical amino acids, biophysical binding assays, cell signaling assays for JAK/STAT phosphorylation\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — site-specific mutagenesis equivalent (photocaged amino acid) with functional signaling readout; single lab, single study\",\n      \"pmids\": [\"37484532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The E3 ubiquitin ligase TRIM21 promotes ubiquitin-dependent degradation of TAp63α, which normally transcriptionally represses IL-20RB by inducing promoter methylation. Loss of TAp63α derepresses IL-20RB, increasing IL-20 receptor formation and activating downstream JAK1-STAT3 signaling to drive PDAC proliferation, EMT, migration, and in vivo metastatic seeding.\",\n      \"method\": \"TAp63α overexpression/knockdown in PDAC cell lines, TRIM21 manipulation, ubiquitination assays, promoter methylation analysis, JAK1-STAT3 western blot, in vivo metastasis model\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ubiquitination, promoter methylation, signaling assays, in vivo model) in a single lab study establishing a regulatory axis upstream of IL-20RB\",\n      \"pmids\": [\"40460193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of IL-20R2 (IL-20RB) in mice reduces psoriasis-like pathological changes induced by imiquimod, confirmed by reduced IL-20R2 protein and mRNA in skin tissue.\",\n      \"method\": \"IL-20R2 knockdown mice, imiquimod-induced psoriasis model, HE staining, western blot, PCR\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss-of-function phenotype without detailed pathway placement; partial knockdown rather than full KO\",\n      \"pmids\": [\"31167692\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-20RB (IL-20R2) is a shared receptor subunit that heterodimerizes with either IL-20R1 or IL-22R1 to form two distinct receptor complexes that bind IL-19, IL-20, and/or IL-24, with structural studies defining the affinity-tuned cytokine-receptor interfaces; ligand engagement activates downstream JAK/STAT3 (and PI3K/Akt) signaling, mediating roles in epidermal homeostasis, psoriasis, pulmonary fibrosis, and cancer progression, while upstream regulation includes transcriptional repression by TAp63α (relieved by TRIM21-mediated degradation) and a functionally critical tyrosine70 residue at the IL-24 binding interface.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL20RB (IL-20R2) is a shared receptor subunit that pairs with either IL-20R1 or IL-22R1 to assemble two distinct heterodimeric receptor complexes, both of which bind IL-24 and signal through STAT transcription factors [#0]. Crystal structures of the IL-20/IL-20R1/IL-20R2 and IL-24/IL-22R1/IL-20R2 ternary complexes define how affinity-tuned cytokine–receptor interfaces allow the single shared IL-20R2 subunit to discriminate among IL-19, IL-20, and IL-24, with IL-20R2 contributing the higher-affinity contact in the type II complex [#2, #3]; tyrosine70 of IL-20R2 is a functionally critical residue at the IL-24/IL-20R2 interface required for heterocomplex assembly and downstream JAK/STAT activation [#9]. Ligand engagement of IL-20RB activates JAK/STAT3 — and in some contexts PI3K/Akt — signaling, a circuit that places the receptor downstream of IL-23 in epidermal hyperplasia and psoriasis-like skin inflammation in mice [#1] and that drives pro-fibrotic macrophage activation in bleomycin-induced pulmonary fibrosis [#8]. The same IL-19/IL-20RB/JAK1-STAT3 axis is co-opted in cancer, where it promotes osteoclast-driven bone metastasis of lung cancer [#6] and stemness, chemoresistance, and metastatic seeding in pancreatic ductal adenocarcinoma [#7, #10]; receptor expression is held in check by TAp63\\u03b1-mediated promoter methylation, which is relieved when TRIM21 degrades TAp63\\u03b1 [#10]. Beyond its cytokine-receptor role, the Toxoplasma gondii rhoptry protein TgROP18 binds the IL-20RB extracellular domain to hijack host JAK/STAT3 signaling [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that IL-20RB is not a standalone receptor but a shared subunit of two heterodimeric complexes, resolving how a single chain serves multiple cytokines.\",\n      \"evidence\": \"Receptor binding assays in transfected COS cells with STAT activation readout in keratinocytes and BHK cells\",\n      \"pmids\": [\"11706020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the atomic interfaces distinguishing the two complexes\", \"Did not assign ligand-specific affinities among IL-19/IL-20/IL-24\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed IL-20RB downstream of IL-23 in an inflammatory cascade, defining its role in epidermal hyperplasia genetically rather than by association.\",\n      \"evidence\": \"Genetic epistasis with IL-20R2-/- knockout mice, intradermal IL-23 injection, histology\",\n      \"pmids\": [\"17074928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which ligand(s) acting through IL-20RB drive the phenotype was not pinpointed\", \"Downstream signaling in skin not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the atomic basis for how the shared IL-20R2 subunit discriminates cognate from noncognate ligands across type I and type II complexes.\",\n      \"evidence\": \"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 ternary complex\",\n      \"pmids\": [\"22802649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure does not capture assembly kinetics\", \"Signaling-competent versus non-productive complex states not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained discrepant knockout phenotypes by identifying an alternatively spliced IL-20RB isoform that survives exon I ablation and retains receptor function.\",\n      \"evidence\": \"Molecular cloning, PCR sequencing, imiquimod psoriasis mouse model\",\n      \"pmids\": [\"27009487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative abundance and tissue distribution of the isoform not quantified\", \"Whether isoforms differ in ligand affinity not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined the type II complex interface, showing a missing disulfide explains IL-24 instability and that IL-20RB is the higher-affinity receptor for IL-24.\",\n      \"evidence\": \"X-ray crystallography of IL-24/IL-22R1/IL-20R2 at 2.15 \\u00c5 with cell-based signaling using refolded IL-24\",\n      \"pmids\": [\"30111632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity ranking rests partly on computational calculation\", \"Single lab structure\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reinforced the requirement for IL-20RB in psoriasis-like skin pathology via knockdown.\",\n      \"evidence\": \"IL-20R2 knockdown mice, imiquimod psoriasis model, histology, western blot, PCR\",\n      \"pmids\": [\"31167692\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Partial knockdown rather than full knockout\", \"No detailed pathway placement\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that a pathogen virulence factor can engage the IL-20RB extracellular domain to commandeer host JAK/STAT3 signaling, extending the receptor's biology beyond cognate cytokines.\",\n      \"evidence\": \"Co-IP, FRET, CRISPR double knockout, recombinant TgROP18 on cell lines with differential IL-20RB expression, phospho-STAT3 western blot\",\n      \"pmids\": [\"32767999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance during infection not established\", \"Binding site on IL-20RB not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an IL-19/IL-20RB/JAK1-STAT3 paracrine axis driving osteoclast-mediated bone metastasis, and showed therapeutic tractability via antibody blockade.\",\n      \"evidence\": \"Gain/loss-of-function in lung cancer lines, in vivo bone metastasis models, neutralizing antibody, JAK1/STAT3 phospho-western blot\",\n      \"pmids\": [\"36006737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability beyond bone microenvironment unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the IL-19/IL-20RB/STAT3 axis to pancreatic cancer stemness and chemoresistance, identifying STAT3 phosphorylation as the actionable node.\",\n      \"evidence\": \"Gain/loss-of-function in PDAC lines, spheroid and side-population assays, in vivo tumor and chemoresistance models, STAT3 inhibition\",\n      \"pmids\": [\"38098005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of other ligands not excluded\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified tyrosine70 of IL-20RB as a functionally critical interface residue using a photocaged amino acid as a reversible switch for complex assembly.\",\n      \"evidence\": \"Genetic code expansion with photocaged ortho-nitrobenzyl-tyrosine, biophysical binding and JAK/STAT signaling assays\",\n      \"pmids\": [\"37484532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single residue tested in isolation\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the upstream transcriptional control of IL-20RB, showing TRIM21-driven degradation of TAp63\\u03b1 derepresses the IL-20RB promoter to fuel PDAC progression.\",\n      \"evidence\": \"TAp63\\u03b1 and TRIM21 manipulation in PDAC lines, ubiquitination assays, promoter methylation analysis, JAK1-STAT3 western blot, in vivo metastasis model\",\n      \"pmids\": [\"40460193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TAp63\\u03b1 occupancy at the promoter versus indirect effects not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ligand-specific IL-20RB signaling outputs are differentially decoded across tissues (skin, lung, bone, pancreas) and whether the two complexes route to distinct downstream programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified comparison of type I versus type II signaling outputs\", \"Ligand-specific transcriptional programs not mapped\", \"Endogenous IL-20RB structural state in signaling-competent membranes not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 10]}\n    ],\n    \"complexes\": [\"IL-20R1/IL-20R2 (type I) receptor\", \"IL-22R1/IL-20R2 (type II) receptor\"],\n    \"partners\": [\"IL20RA\", \"IL22RA1\", \"IL24\", \"IL20\", \"IL19\", \"TgROP18\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}