{"gene":"IL20RB","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2001,"finding":"IL-20RB (IL-20R2) forms two distinct heterodimeric receptor complexes—IL-22R1/IL-20R2 and IL-20R1/IL-20R2—that both serve as functional receptors for IL-24, with binding leading to activation of STAT transcription factors in keratinocytes and BHK cells.","method":"Ligand binding assays on transfected COS cells, STAT activation assays in keratinocytes and BHK cells expressing ectopic receptors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding and functional STAT activation assays with endogenous and ectopic receptors, replicated across cell types","pmids":["11706020"],"is_preprint":false},{"year":2006,"finding":"IL-20R2 (IL-20RB) is required downstream of IL-23 for epidermal hyperplasia in mouse skin; IL-23-induced epidermal hyperplasia was abolished in IL-20R2-/- mice but not in IL-19-/- or IL-24-/- single knockouts, placing IL-20R2 as a non-redundant effector in the IL-23 → IL-20 subfamily cytokine → epidermal hyperplasia pathway.","method":"Intradermal IL-23 injection in IL-20R2-/-, IL-19-/-, and IL-24-/- mice with histological readout of epidermal hyperplasia","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple single-knockout controls, strong phenotypic readout, highly cited","pmids":["17074928"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex reveals the molecular basis for shared IL-20R2 usage by three cytokines (IL-19, IL-20, IL-24): receptor-cytokine interfaces are affinity-tuned to allow discrimination of cognate from noncognate ligands across type I (IL-20R1/IL-20R2) and type II (IL-22R1/IL-20R2) complexes.","method":"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 ternary complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional interpretation of binding interfaces, published in high-impact journal","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 cysteines in IL-24 do not form a predicted disulfide bond, explaining IL-24 instability, and reveals that the IL-24–IL-20R2 interface is slightly more stable than the IL-24–IL-22R1 interface, suggesting IL-20R2 is the higher-affinity receptor in this complex.","method":"X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex; cell-based STAT activation assay to confirm IL-24 activity","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at 2.15 Å with functional validation and energetic calculations","pmids":["30111632"],"is_preprint":false},{"year":2016,"finding":"Alternative splicing of the IL-20R2 (IL-20RB) gene produces two isoforms; deletion of exon I leaves the alternatively spliced isoform intact, explaining why exon I knockout mice showed an incomplete loss of IL-20R2-dependent psoriatic phenotypes.","method":"Molecular cloning of alternatively spliced transcript, PCR sequencing, western blot, imiquimod-induced psoriasis mouse model","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — molecular identification of novel isoform explaining in vivo phenotypic discrepancy, single lab","pmids":["27009487"],"is_preprint":false},{"year":2020,"finding":"Toxoplasma gondii rhoptry protein TgROP18 physically interacts with the extracellular domain of IL-20RB and activates the host JAK/STAT3 pathway through this interaction; STAT3 phosphorylation by recombinant ROP18 was only observed in cells with endogenous IL-20RB expression, and the effect was dose-dependent.","method":"FRET, co-immunoprecipitation, CRISPR-Cas9 double-knockout parasite strain (RH-Δrop16Δrop18), western blot of STAT3 phosphorylation in IL-20RB-positive vs. negative cell lines","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and FRET confirming direct interaction; functional link via cell-line comparison and dose-response","pmids":["32767999"],"is_preprint":false},{"year":2022,"finding":"IL-20RB mediates IL-19-driven JAK1/STAT3 signaling in lung cancer cells in the bone metastatic niche; tumor cells induce osteoclasts to secrete IL-19, which activates IL-20RB on tumor cells to promote proliferation, and a neutralizing anti-IL-20RB antibody suppressed 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":"High","confidence_rationale":"Tier 2 — loss-of-function, gain-of-function, in vivo rescue with neutralizing antibody, and defined downstream signaling, moderate evidence from single lab with multiple orthogonal methods","pmids":["36006737"],"is_preprint":false},{"year":2023,"finding":"IL-20RB promotes stemness and chemotherapy resistance in pancreatic cancer by activating STAT3 phosphorylation downstream of IL-19 (its primary microenvironmental ligand); STAT3 phosphorylation inhibitors counteracted these effects.","method":"IL-20RB overexpression and knockdown in pancreatic cancer cell lines, clonal/spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with pathway-level rescue by STAT3 inhibitor; single lab, multiple orthogonal in vitro and in vivo methods","pmids":["38098005"],"is_preprint":false},{"year":2023,"finding":"Introduction of a photocaged non-canonical amino acid (ortho-nitrobenzyl-tyrosine) at tyrosine70 of IL-20R2 impairs IL-24/IL-20R2 heterocomplex assembly; UV irradiation restores native tyrosine and reconstitutes JAK/STAT signaling, demonstrating that tyrosine70 is critical for IL-24 binding to IL-20R2.","method":"Genetic code expansion/photocaged amino acid incorporation, biophysical binding assays, cell signaling (STAT phosphorylation) assays","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 1 — site-specific mutagenesis equivalent via photocaging with functional rescue; single lab, proof-of-concept study","pmids":["37484532"],"is_preprint":false},{"year":2024,"finding":"IL-20RB promotes profibrotic macrophage (M2-like) polarization and pulmonary fibrosis by activating JAK2/STAT3 and PI3K/Akt signaling pathways; IL-20RB knockdown or neutralizing antibody treatment attenuated bleomycin-induced fibrosis.","method":"Bleomycin-induced pulmonary fibrosis model, IL4/IL-13-induced THP1 M2 polarization model, IL-20RB knockdown, neutralizing antibody treatment, western blot for JAK2/STAT3 and PI3K/Akt","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro models with defined downstream signaling; single lab with multiple orthogonal approaches","pmids":["38583686"],"is_preprint":false},{"year":2025,"finding":"TAp63α transcriptionally represses IL-20RB expression (potentially via promoter methylation); TRIM21 E3 ligase promotes ubiquitin-dependent degradation of TAp63α, thereby derepressing IL-20RB and enabling IL-20 receptor complex formation and downstream JAK1-STAT3 activation that drives PDAC cell proliferation, EMT, migration, and metastatic seeding.","method":"TRIM21 and TAp63α overexpression/knockdown in PDAC cell lines, promoter methylation analysis, ubiquitination assays, STAT3 phosphorylation western blot, in vivo metastasis seeding assay","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 — defines upstream regulatory axis of IL-20RB with ubiquitination, promoter, and in vivo functional data; single lab","pmids":["40460193"],"is_preprint":false},{"year":2019,"finding":"Knockdown of IL-20R2 in mice significantly reduces imiquimod-induced psoriasis-like skin pathology, confirming an essential role of IL-20RB signaling in keratinocyte-driven epidermal inflammation.","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":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific histological phenotype; single lab, single method approach","pmids":["31167692"],"is_preprint":false},{"year":2022,"finding":"In grass carp (teleost ortholog), IL-20R2 binds directly to IL-20 (shown by co-immunoprecipitation), while IL-20R1 is responsible for STAT3 phosphorylation signaling; key residues at the IL-20/receptor interface are conserved between fish and human, suggesting conserved receptor assembly mechanism.","method":"Co-immunoprecipitation, STAT3 phosphorylation western blot, structural modeling","journal":"Fish & shellfish immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding shown by Co-IP with functional separation of receptor subunit roles; fish ortholog with conserved residues","pmids":["36414129"],"is_preprint":false}],"current_model":"IL-20RB (IL-20R2) is a shared receptor subunit that partners with either IL-20R1 or IL-22R1 to form heterodimeric complexes that bind IL-19, IL-20, and/or IL-24 with affinity-tuned interfaces defined by crystal structures, triggering JAK1/STAT3 (and JAK2/PI3K-Akt) signaling in keratinocytes, macrophages, and tumor cells; its expression is transcriptionally repressed by TAp63α (itself degraded by TRIM21), and it plays non-redundant roles in IL-23-driven epidermal hyperplasia, psoriasis, pulmonary fibrosis, and cancer metastasis as shown by genetic knockout, neutralizing antibody, and epistasis experiments."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that IL-20RB is a shared receptor subunit resolved how IL-24 signals through two distinct heterodimeric complexes (IL-20R1/IL-20R2 and IL-22R1/IL-20R2) to activate STAT transcription factors.","evidence":"Ligand binding assays on transfected COS cells and STAT activation assays in keratinocytes and BHK cells","pmids":["11706020"],"confidence":"High","gaps":["Relative contributions of each heterodimer to IL-24 signaling in physiological tissues unknown","Signaling specificity downstream of each complex not resolved"]},{"year":2006,"claim":"Demonstrating that IL-20R2 knockout abolished IL-23-induced epidermal hyperplasia — while single IL-19 or IL-24 knockouts did not — established IL-20RB as a non-redundant signaling node integrating multiple IL-20 subfamily ligands in skin inflammation.","evidence":"Intradermal IL-23 injection in IL-20R2−/−, IL-19−/−, and IL-24−/− mice with histological readout","pmids":["17074928"],"confidence":"High","gaps":["Which individual IL-20 subfamily ligand(s) are essential downstream of IL-23 remained unresolved","Cellular source of ligands in the epidermal niche not defined"]},{"year":2012,"claim":"The crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex provided the first atomic-level explanation for how IL-20RB serves as a shared subunit for three cytokines through affinity-tuned binding interfaces.","evidence":"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 complex","pmids":["22802649"],"confidence":"High","gaps":["Structure of the IL-19-containing complex not determined","How affinity differences translate to signaling kinetics in vivo not tested"]},{"year":2016,"claim":"Discovery of an alternatively spliced IL-20RB isoform that escapes exon I deletion explained why earlier knockout mice showed incomplete psoriatic phenotypes, revealing a layer of transcript-level regulation.","evidence":"Cloning of alternative transcript, PCR, western blot, imiquimod psoriasis model in exon I knockout mice","pmids":["27009487"],"confidence":"Medium","gaps":["Functional activity and signaling competence of the alternative isoform not fully characterized","Tissue distribution of isoforms not comprehensively mapped"]},{"year":2018,"claim":"The 2.15 Å structure of the IL-24/IL-22R1/IL-20R2 complex revealed that IL-20R2 is the higher-affinity subunit in this complex and explained IL-24 instability through unpaired cysteines, completing the structural picture of both IL-20RB-containing receptor assemblies.","evidence":"X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex with STAT activation validation","pmids":["30111632"],"confidence":"High","gaps":["No IL-19/receptor complex structure available for comparison","How differential affinity governs cell-type-specific responses not addressed"]},{"year":2019,"claim":"IL-20R2 knockdown attenuated imiquimod-induced psoriasis in mice, independently confirming the non-redundant requirement for IL-20RB signaling in keratinocyte-driven epidermal inflammation first observed in full knockouts.","evidence":"IL-20R2 knockdown mice, imiquimod psoriasis model, histology and western blot","pmids":["31167692"],"confidence":"Medium","gaps":["Knockdown efficiency and residual IL-20RB activity not precisely quantified","Relative contribution of macrophage vs. keratinocyte IL-20RB not dissected"]},{"year":2020,"claim":"Identification of Toxoplasma gondii ROP18 as an exogenous activator that co-opts IL-20RB to trigger host JAK/STAT3 signaling expanded the receptor's biology beyond endogenous cytokine signaling to pathogen exploitation.","evidence":"FRET, co-immunoprecipitation, STAT3 phosphorylation in IL-20RB-positive vs. IL-20RB-negative cell lines using CRISPR knockout parasites","pmids":["32767999"],"confidence":"Medium","gaps":["In vivo relevance during Toxoplasma infection not demonstrated","Binding site on IL-20RB for ROP18 not structurally defined"]},{"year":2022,"claim":"Showing that IL-19/IL-20RB signaling through JAK1/STAT3 in the bone metastatic niche drives lung cancer cell proliferation — suppressible by neutralizing anti-IL-20RB antibody — established a tumor-extrinsic paracrine loop and therapeutic vulnerability.","evidence":"IL-20RB overexpression/knockdown in lung cancer cells, in vivo bone metastasis model, neutralizing antibody, JAK1/STAT3 western blot","pmids":["36006737"],"confidence":"High","gaps":["Patient-derived data on IL-20RB expression in bone metastases limited","Contribution of IL-20 and IL-24 ligands to the same niche not separated"]},{"year":2023,"claim":"Photocaging of tyrosine 70 in IL-20R2 blocked IL-24 binding and signaling, with UV-mediated restoration proving that this single residue is a critical determinant of ligand–receptor complex assembly.","evidence":"Genetic code expansion with ortho-nitrobenzyl-tyrosine incorporation, biophysical binding and STAT phosphorylation assays","pmids":["37484532"],"confidence":"Medium","gaps":["Whether Y70 is equally important for IL-19 or IL-20 binding not tested","Approach not validated in primary cells"]},{"year":2023,"claim":"IL-20RB/STAT3 signaling was shown to promote cancer stemness and chemoresistance in pancreatic cancer, broadening the receptor's oncogenic roles beyond metastasis to treatment resistance.","evidence":"IL-20RB overexpression/knockdown in pancreatic cancer cells, spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue","pmids":["38098005"],"confidence":"Medium","gaps":["Identity of microenvironmental cells supplying IL-19 in pancreatic tumors not defined","Whether other IL-20 subfamily members contribute equally not resolved"]},{"year":2024,"claim":"Demonstrating that IL-20RB drives profibrotic M2-like macrophage polarization via JAK2/STAT3 and PI3K/Akt signaling extended its pathological roles to pulmonary fibrosis and identified JAK2 as an additional kinase partner beyond JAK1.","evidence":"Bleomycin-induced pulmonary fibrosis model, THP1 macrophage polarization, IL-20RB knockdown and neutralizing antibody, JAK2/STAT3 and PI3K/Akt western blot","pmids":["38583686"],"confidence":"Medium","gaps":["Whether JAK2 directly associates with IL-20RB or with IL-20R1 not biochemically resolved","Ligand identity driving macrophage IL-20RB signaling in fibrotic lung not pinpointed"]},{"year":2025,"claim":"Discovery that TRIM21-mediated ubiquitin degradation of TAp63α derepresses IL-20RB transcription defined the first upstream regulatory axis controlling IL-20RB expression and linked it to PDAC metastasis.","evidence":"TRIM21/TAp63α overexpression/knockdown, promoter methylation analysis, ubiquitination assays, in vivo metastasis seeding in PDAC models","pmids":["40460193"],"confidence":"Medium","gaps":["Direct TAp63α binding to IL-20RB promoter not shown by ChIP","Whether this regulatory axis operates in non-tumor tissues not examined"]},{"year":null,"claim":"How the two IL-20RB-containing receptor complexes (type I and type II) differentially activate downstream transcriptional programs in specific cell types, and the structural basis of IL-19 recognition by IL-20RB, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of an IL-19-containing receptor complex","Cell-type-specific signaling outputs of the two receptor complexes not systematically compared","Role of alternative IL-20RB isoform in disease contexts unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,3,6]}],"pathway":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]}],"complexes":["IL-20R1/IL-20R2 type I receptor complex","IL-22R1/IL-20R2 type II receptor complex"],"partners":["IL20R1","IL22R1","IL19","IL20","IL24","JAK1","STAT3","TAP63"],"other_free_text":[]},"mechanistic_narrative":"IL-20RB (IL-20R2) is a shared cytokine receptor subunit that heterodimerizes with either IL-20R1 or IL-22R1 to transduce signals from the IL-20 subfamily cytokines IL-19, IL-20, and IL-24, activating JAK1/STAT3 (and JAK2/PI3K-Akt) cascades in keratinocytes, macrophages, and tumor cells [PMID:11706020, PMID:36006737, PMID:38583686]. Crystal structures of the IL-20/IL-20R1/IL-20R2 and IL-24/IL-22R1/IL-20R2 ternary complexes reveal affinity-tuned binding interfaces that allow IL-20RB to discriminate among its three cognate ligands, with tyrosine 70 of IL-20R2 serving as a critical contact residue for IL-24 binding [PMID:22802649, PMID:30111632, PMID:37484532]. IL-20RB is non-redundantly required downstream of IL-23 for epidermal hyperplasia and psoriasis-like pathology, and it drives profibrotic macrophage polarization in pulmonary fibrosis as well as cancer stemness, chemoresistance, and bone metastasis in lung and pancreatic cancers [PMID:17074928, PMID:31167692, PMID:38583686, PMID:36006737, PMID:38098005]. IL-20RB expression is transcriptionally repressed by TAp63α, which is itself targeted for ubiquitin-dependent degradation by the E3 ligase TRIM21, linking upstream proteasomal control to IL-20RB-dependent STAT3 activation and metastatic progression [PMID:40460193]."},"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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interleukin-20 receptor-2 (IL-20R2) binding cytokines.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22802649","citation_count":77,"is_preprint":false},{"pmid":"36006737","id":"PMC_36006737","title":"IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36006737","citation_count":76,"is_preprint":false},{"pmid":"16093711","id":"PMC_16093711","title":"DIRS-1 and the other tyrosine recombinase retrotransposons.","date":"2005","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16093711","citation_count":55,"is_preprint":false},{"pmid":"23146749","id":"PMC_23146749","title":"ALOG domains: provenance of plant homeotic and developmental regulators from the DNA-binding domain of a novel class of DIRS1-type 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biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37484532","citation_count":7,"is_preprint":false},{"pmid":"40460193","id":"PMC_40460193","title":"The E3 ligase TRIM21 promotes progression of pancreatic ductal adenocarcinoma by down-regulating TAp63α and derepressing IL20RB.","date":"2025","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/40460193","citation_count":6,"is_preprint":false},{"pmid":"36414129","id":"PMC_36414129","title":"Grass carp IL-20 binds to IL-20R2 but induces STAT3 phosphorylation via IL-20R1.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36414129","citation_count":6,"is_preprint":false},{"pmid":"36225230","id":"PMC_36225230","title":"The IL-20RB receptor and the IL-20 signaling pathway in regulating host defense in oral mucosal candidiasis.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36225230","citation_count":5,"is_preprint":false},{"pmid":"23811545","id":"PMC_23811545","title":"Detection of IL-20R1 and IL-20R2 mRNA in C57BL/6 mice astroglial cells and brain cortex following LPS stimulation.","date":"2013","source":"Iranian journal of immunology : IJI","url":"https://pubmed.ncbi.nlm.nih.gov/23811545","citation_count":4,"is_preprint":false},{"pmid":"27009487","id":"PMC_27009487","title":"Alternative splicing directs two IL-20R2 isoforms and is responsible for the incomplete gene knockout via the exon I ablation.","date":"2016","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27009487","citation_count":2,"is_preprint":false},{"pmid":"31167692","id":"PMC_31167692","title":"[Knockdown of interleukin 20 receptor 2 (IL-20R2) inhibits the development of psoriasis induced by imiquimod in mice].","date":"2019","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular 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":14743,"output_tokens":3323,"usd":0.047037},"stage2":{"model":"claude-opus-4-6","input_tokens":6737,"output_tokens":6291,"usd":0.28644},"total_usd":0.333477,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-20RB (IL-20R2) forms two distinct heterodimeric receptor complexes—IL-22R1/IL-20R2 and IL-20R1/IL-20R2—that both serve as functional receptors for IL-24, with binding leading to activation of STAT transcription factors in keratinocytes and BHK cells.\",\n      \"method\": \"Ligand binding assays on transfected COS cells, STAT activation assays in keratinocytes and BHK cells expressing ectopic receptors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding and functional STAT activation assays with endogenous and ectopic receptors, replicated across cell types\",\n      \"pmids\": [\"11706020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-20R2 (IL-20RB) is required downstream of IL-23 for epidermal hyperplasia in mouse skin; IL-23-induced epidermal hyperplasia was abolished in IL-20R2-/- mice but not in IL-19-/- or IL-24-/- single knockouts, placing IL-20R2 as a non-redundant effector in the IL-23 → IL-20 subfamily cytokine → epidermal hyperplasia pathway.\",\n      \"method\": \"Intradermal IL-23 injection in IL-20R2-/-, IL-19-/-, and IL-24-/- mice with histological readout of epidermal hyperplasia\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple single-knockout controls, strong phenotypic readout, highly cited\",\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 the molecular basis for shared IL-20R2 usage by three cytokines (IL-19, IL-20, IL-24): receptor-cytokine interfaces are affinity-tuned to allow discrimination of cognate from noncognate ligands across type I (IL-20R1/IL-20R2) and type II (IL-22R1/IL-20R2) complexes.\",\n      \"method\": \"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 ternary complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional interpretation of binding interfaces, published in high-impact journal\",\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 cysteines in IL-24 do not form a predicted disulfide bond, explaining IL-24 instability, and reveals that the IL-24–IL-20R2 interface is slightly more stable than the IL-24–IL-22R1 interface, suggesting IL-20R2 is the higher-affinity receptor in this complex.\",\n      \"method\": \"X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex; cell-based STAT activation assay to confirm IL-24 activity\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.15 Å with functional validation and energetic calculations\",\n      \"pmids\": [\"30111632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Alternative splicing of the IL-20R2 (IL-20RB) gene produces two isoforms; deletion of exon I leaves the alternatively spliced isoform intact, explaining why exon I knockout mice showed an incomplete loss of IL-20R2-dependent psoriatic phenotypes.\",\n      \"method\": \"Molecular cloning of alternatively spliced transcript, PCR sequencing, western blot, imiquimod-induced psoriasis mouse model\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular identification of novel isoform explaining in vivo phenotypic discrepancy, 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 and activates the host JAK/STAT3 pathway through this interaction; STAT3 phosphorylation by recombinant ROP18 was only observed in cells with endogenous IL-20RB expression, and the effect was dose-dependent.\",\n      \"method\": \"FRET, co-immunoprecipitation, CRISPR-Cas9 double-knockout parasite strain (RH-Δrop16Δrop18), western blot of STAT3 phosphorylation in IL-20RB-positive vs. negative cell lines\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and FRET confirming direct interaction; functional link via cell-line comparison and dose-response\",\n      \"pmids\": [\"32767999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-20RB mediates IL-19-driven JAK1/STAT3 signaling in lung cancer cells in the bone metastatic niche; tumor cells induce osteoclasts to secrete IL-19, which activates IL-20RB on tumor cells to promote proliferation, and a neutralizing anti-IL-20RB antibody suppressed 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\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function, gain-of-function, in vivo rescue with neutralizing antibody, and defined downstream signaling, moderate evidence from single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36006737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-20RB promotes stemness and chemotherapy resistance in pancreatic cancer by activating STAT3 phosphorylation downstream of IL-19 (its primary microenvironmental ligand); STAT3 phosphorylation inhibitors counteracted these effects.\",\n      \"method\": \"IL-20RB overexpression and knockdown in pancreatic cancer cell lines, clonal/spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with pathway-level rescue by STAT3 inhibitor; single lab, multiple orthogonal in vitro and in vivo methods\",\n      \"pmids\": [\"38098005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Introduction of a photocaged non-canonical amino acid (ortho-nitrobenzyl-tyrosine) at tyrosine70 of IL-20R2 impairs IL-24/IL-20R2 heterocomplex assembly; UV irradiation restores native tyrosine and reconstitutes JAK/STAT signaling, demonstrating that tyrosine70 is critical for IL-24 binding to IL-20R2.\",\n      \"method\": \"Genetic code expansion/photocaged amino acid incorporation, biophysical binding assays, cell signaling (STAT phosphorylation) assays\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis equivalent via photocaging with functional rescue; single lab, proof-of-concept study\",\n      \"pmids\": [\"37484532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-20RB promotes profibrotic macrophage (M2-like) polarization and pulmonary fibrosis by activating JAK2/STAT3 and PI3K/Akt signaling pathways; IL-20RB knockdown or neutralizing antibody treatment attenuated bleomycin-induced fibrosis.\",\n      \"method\": \"Bleomycin-induced pulmonary fibrosis model, IL4/IL-13-induced THP1 M2 polarization model, IL-20RB knockdown, neutralizing antibody treatment, western blot for JAK2/STAT3 and PI3K/Akt\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro models with defined downstream signaling; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38583686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAp63α transcriptionally represses IL-20RB expression (potentially via promoter methylation); TRIM21 E3 ligase promotes ubiquitin-dependent degradation of TAp63α, thereby derepressing IL-20RB and enabling IL-20 receptor complex formation and downstream JAK1-STAT3 activation that drives PDAC cell proliferation, EMT, migration, and metastatic seeding.\",\n      \"method\": \"TRIM21 and TAp63α overexpression/knockdown in PDAC cell lines, promoter methylation analysis, ubiquitination assays, STAT3 phosphorylation western blot, in vivo metastasis seeding assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defines upstream regulatory axis of IL-20RB with ubiquitination, promoter, and in vivo functional data; single lab\",\n      \"pmids\": [\"40460193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of IL-20R2 in mice significantly reduces imiquimod-induced psoriasis-like skin pathology, confirming an essential role of IL-20RB signaling in keratinocyte-driven epidermal inflammation.\",\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\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific histological phenotype; single lab, single method approach\",\n      \"pmids\": [\"31167692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In grass carp (teleost ortholog), IL-20R2 binds directly to IL-20 (shown by co-immunoprecipitation), while IL-20R1 is responsible for STAT3 phosphorylation signaling; key residues at the IL-20/receptor interface are conserved between fish and human, suggesting conserved receptor assembly mechanism.\",\n      \"method\": \"Co-immunoprecipitation, STAT3 phosphorylation western blot, structural modeling\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown by Co-IP with functional separation of receptor subunit roles; fish ortholog with conserved residues\",\n      \"pmids\": [\"36414129\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-20RB (IL-20R2) is a shared receptor subunit that partners with either IL-20R1 or IL-22R1 to form heterodimeric complexes that bind IL-19, IL-20, and/or IL-24 with affinity-tuned interfaces defined by crystal structures, triggering JAK1/STAT3 (and JAK2/PI3K-Akt) signaling in keratinocytes, macrophages, and tumor cells; its expression is transcriptionally repressed by TAp63α (itself degraded by TRIM21), and it plays non-redundant roles in IL-23-driven epidermal hyperplasia, psoriasis, pulmonary fibrosis, and cancer metastasis as shown by genetic knockout, neutralizing antibody, and epistasis experiments.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-20RB (IL-20R2) is a shared cytokine receptor subunit that heterodimerizes with either IL-20R1 or IL-22R1 to transduce signals from the IL-20 subfamily cytokines IL-19, IL-20, and IL-24, activating JAK1/STAT3 (and JAK2/PI3K-Akt) cascades in keratinocytes, macrophages, and tumor cells [PMID:11706020, PMID:36006737, PMID:38583686]. Crystal structures of the IL-20/IL-20R1/IL-20R2 and IL-24/IL-22R1/IL-20R2 ternary complexes reveal affinity-tuned binding interfaces that allow IL-20RB to discriminate among its three cognate ligands, with tyrosine 70 of IL-20R2 serving as a critical contact residue for IL-24 binding [PMID:22802649, PMID:30111632, PMID:37484532]. IL-20RB is non-redundantly required downstream of IL-23 for epidermal hyperplasia and psoriasis-like pathology, and it drives profibrotic macrophage polarization in pulmonary fibrosis as well as cancer stemness, chemoresistance, and bone metastasis in lung and pancreatic cancers [PMID:17074928, PMID:31167692, PMID:38583686, PMID:36006737, PMID:38098005]. IL-20RB expression is transcriptionally repressed by TAp63α, which is itself targeted for ubiquitin-dependent degradation by the E3 ligase TRIM21, linking upstream proteasomal control to IL-20RB-dependent STAT3 activation and metastatic progression [PMID:40460193].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that IL-20RB is a shared receptor subunit resolved how IL-24 signals through two distinct heterodimeric complexes (IL-20R1/IL-20R2 and IL-22R1/IL-20R2) to activate STAT transcription factors.\",\n      \"evidence\": \"Ligand binding assays on transfected COS cells and STAT activation assays in keratinocytes and BHK cells\",\n      \"pmids\": [\"11706020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of each heterodimer to IL-24 signaling in physiological tissues unknown\", \"Signaling specificity downstream of each complex not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that IL-20R2 knockout abolished IL-23-induced epidermal hyperplasia — while single IL-19 or IL-24 knockouts did not — established IL-20RB as a non-redundant signaling node integrating multiple IL-20 subfamily ligands in skin inflammation.\",\n      \"evidence\": \"Intradermal IL-23 injection in IL-20R2−/−, IL-19−/−, and IL-24−/− mice with histological readout\",\n      \"pmids\": [\"17074928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which individual IL-20 subfamily ligand(s) are essential downstream of IL-23 remained unresolved\", \"Cellular source of ligands in the epidermal niche not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex provided the first atomic-level explanation for how IL-20RB serves as a shared subunit for three cytokines through affinity-tuned binding interfaces.\",\n      \"evidence\": \"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 complex\",\n      \"pmids\": [\"22802649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the IL-19-containing complex not determined\", \"How affinity differences translate to signaling kinetics in vivo not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of an alternatively spliced IL-20RB isoform that escapes exon I deletion explained why earlier knockout mice showed incomplete psoriatic phenotypes, revealing a layer of transcript-level regulation.\",\n      \"evidence\": \"Cloning of alternative transcript, PCR, western blot, imiquimod psoriasis model in exon I knockout mice\",\n      \"pmids\": [\"27009487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional activity and signaling competence of the alternative isoform not fully characterized\", \"Tissue distribution of isoforms not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The 2.15 Å structure of the IL-24/IL-22R1/IL-20R2 complex revealed that IL-20R2 is the higher-affinity subunit in this complex and explained IL-24 instability through unpaired cysteines, completing the structural picture of both IL-20RB-containing receptor assemblies.\",\n      \"evidence\": \"X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex with STAT activation validation\",\n      \"pmids\": [\"30111632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No IL-19/receptor complex structure available for comparison\", \"How differential affinity governs cell-type-specific responses not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL-20R2 knockdown attenuated imiquimod-induced psoriasis in mice, independently confirming the non-redundant requirement for IL-20RB signaling in keratinocyte-driven epidermal inflammation first observed in full knockouts.\",\n      \"evidence\": \"IL-20R2 knockdown mice, imiquimod psoriasis model, histology and western blot\",\n      \"pmids\": [\"31167692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown efficiency and residual IL-20RB activity not precisely quantified\", \"Relative contribution of macrophage vs. keratinocyte IL-20RB not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of Toxoplasma gondii ROP18 as an exogenous activator that co-opts IL-20RB to trigger host JAK/STAT3 signaling expanded the receptor's biology beyond endogenous cytokine signaling to pathogen exploitation.\",\n      \"evidence\": \"FRET, co-immunoprecipitation, STAT3 phosphorylation in IL-20RB-positive vs. IL-20RB-negative cell lines using CRISPR knockout parasites\",\n      \"pmids\": [\"32767999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance during Toxoplasma infection not demonstrated\", \"Binding site on IL-20RB for ROP18 not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that IL-19/IL-20RB signaling through JAK1/STAT3 in the bone metastatic niche drives lung cancer cell proliferation — suppressible by neutralizing anti-IL-20RB antibody — established a tumor-extrinsic paracrine loop and therapeutic vulnerability.\",\n      \"evidence\": \"IL-20RB overexpression/knockdown in lung cancer cells, in vivo bone metastasis model, neutralizing antibody, JAK1/STAT3 western blot\",\n      \"pmids\": [\"36006737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Patient-derived data on IL-20RB expression in bone metastases limited\", \"Contribution of IL-20 and IL-24 ligands to the same niche not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Photocaging of tyrosine 70 in IL-20R2 blocked IL-24 binding and signaling, with UV-mediated restoration proving that this single residue is a critical determinant of ligand–receptor complex assembly.\",\n      \"evidence\": \"Genetic code expansion with ortho-nitrobenzyl-tyrosine incorporation, biophysical binding and STAT phosphorylation assays\",\n      \"pmids\": [\"37484532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Y70 is equally important for IL-19 or IL-20 binding not tested\", \"Approach not validated in primary cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IL-20RB/STAT3 signaling was shown to promote cancer stemness and chemoresistance in pancreatic cancer, broadening the receptor's oncogenic roles beyond metastasis to treatment resistance.\",\n      \"evidence\": \"IL-20RB overexpression/knockdown in pancreatic cancer cells, spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue\",\n      \"pmids\": [\"38098005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of microenvironmental cells supplying IL-19 in pancreatic tumors not defined\", \"Whether other IL-20 subfamily members contribute equally not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that IL-20RB drives profibrotic M2-like macrophage polarization via JAK2/STAT3 and PI3K/Akt signaling extended its pathological roles to pulmonary fibrosis and identified JAK2 as an additional kinase partner beyond JAK1.\",\n      \"evidence\": \"Bleomycin-induced pulmonary fibrosis model, THP1 macrophage polarization, IL-20RB knockdown and neutralizing antibody, JAK2/STAT3 and PI3K/Akt western blot\",\n      \"pmids\": [\"38583686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAK2 directly associates with IL-20RB or with IL-20R1 not biochemically resolved\", \"Ligand identity driving macrophage IL-20RB signaling in fibrotic lung not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that TRIM21-mediated ubiquitin degradation of TAp63α derepresses IL-20RB transcription defined the first upstream regulatory axis controlling IL-20RB expression and linked it to PDAC metastasis.\",\n      \"evidence\": \"TRIM21/TAp63α overexpression/knockdown, promoter methylation analysis, ubiquitination assays, in vivo metastasis seeding in PDAC models\",\n      \"pmids\": [\"40460193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TAp63α binding to IL-20RB promoter not shown by ChIP\", \"Whether this regulatory axis operates in non-tumor tissues not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two IL-20RB-containing receptor complexes (type I and type II) differentially activate downstream transcriptional programs in specific cell types, and the structural basis of IL-19 recognition by IL-20RB, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of an IL-19-containing receptor complex\", \"Cell-type-specific signaling outputs of the two receptor complexes not systematically compared\", \"Role of alternative IL-20RB isoform in disease contexts unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"IL-20R1/IL-20R2 type I receptor complex\",\n      \"IL-22R1/IL-20R2 type II receptor complex\"\n    ],\n    \"partners\": [\n      \"IL20R1\",\n      \"IL22R1\",\n      \"IL19\",\n      \"IL20\",\n      \"IL24\",\n      \"JAK1\",\n      \"STAT3\",\n      \"TAP63\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to correct the pathway entries. The pathway should use Reactome IDs, not GO IDs. Let me fix:\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-20RB (IL-20R2) is a shared cytokine receptor subunit that heterodimerizes with either IL-20R1 or IL-22R1 to transduce signals from the IL-20 subfamily cytokines IL-19, IL-20, and IL-24, activating JAK1/STAT3 (and JAK2/PI3K-Akt) cascades in keratinocytes, macrophages, and tumor cells [PMID:11706020, PMID:36006737, PMID:38583686]. Crystal structures of the IL-20/IL-20R1/IL-20R2 and IL-24/IL-22R1/IL-20R2 ternary complexes reveal affinity-tuned binding interfaces that allow IL-20RB to discriminate among its three cognate ligands, with tyrosine 70 of IL-20R2 serving as a critical contact residue for IL-24 binding [PMID:22802649, PMID:30111632, PMID:37484532]. IL-20RB is non-redundantly required downstream of IL-23 for epidermal hyperplasia and psoriasis-like pathology, and it drives profibrotic macrophage polarization in pulmonary fibrosis as well as cancer stemness, chemoresistance, and bone metastasis in lung and pancreatic cancers [PMID:17074928, PMID:31167692, PMID:38583686, PMID:36006737, PMID:38098005]. IL-20RB expression is transcriptionally repressed by TAp63α, which is itself targeted for ubiquitin-dependent degradation by the E3 ligase TRIM21, linking upstream proteasomal control to IL-20RB-dependent STAT3 activation and metastatic progression [PMID:40460193].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that IL-20RB is a shared receptor subunit resolved how IL-24 signals through two distinct heterodimeric complexes (IL-20R1/IL-20R2 and IL-22R1/IL-20R2) to activate STAT transcription factors.\",\n      \"evidence\": \"Ligand binding assays on transfected COS cells and STAT activation assays in keratinocytes and BHK cells\",\n      \"pmids\": [\"11706020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of each heterodimer to IL-24 signaling in physiological tissues unknown\", \"Signaling specificity downstream of each complex not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that IL-20R2 knockout abolished IL-23-induced epidermal hyperplasia — while single IL-19 or IL-24 knockouts did not — established IL-20RB as a non-redundant signaling node integrating multiple IL-20 subfamily ligands in skin inflammation.\",\n      \"evidence\": \"Intradermal IL-23 injection in IL-20R2−/−, IL-19−/−, and IL-24−/− mice with histological readout\",\n      \"pmids\": [\"17074928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which individual IL-20 subfamily ligand(s) are essential downstream of IL-23 remained unresolved\", \"Cellular source of ligands in the epidermal niche not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The crystal structure of the IL-20/IL-20R1/IL-20R2 ternary complex provided the first atomic-level explanation for how IL-20RB serves as a shared subunit for three cytokines through affinity-tuned binding interfaces.\",\n      \"evidence\": \"X-ray crystallography of the IL-20/IL-20R1/IL-20R2 complex\",\n      \"pmids\": [\"22802649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the IL-19-containing complex not determined\", \"How affinity differences translate to signaling kinetics in vivo not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery of an alternatively spliced IL-20RB isoform that escapes exon I deletion explained why earlier knockout mice showed incomplete psoriatic phenotypes, revealing a layer of transcript-level regulation.\",\n      \"evidence\": \"Cloning of alternative transcript, PCR, western blot, imiquimod psoriasis model in exon I knockout mice\",\n      \"pmids\": [\"27009487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional activity and signaling competence of the alternative isoform not fully characterized\", \"Tissue distribution of isoforms not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The 2.15 Å structure of the IL-24/IL-22R1/IL-20R2 complex revealed that IL-20R2 is the higher-affinity subunit in this complex and explained IL-24 instability through unpaired cysteines, completing the structural picture of both IL-20RB-containing receptor assemblies.\",\n      \"evidence\": \"X-ray crystallography of fusion-stabilized IL-24/IL-22R1/IL-20R2 complex with STAT activation validation\",\n      \"pmids\": [\"30111632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No IL-19/receptor complex structure available for comparison\", \"How differential affinity governs cell-type-specific responses not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL-20R2 knockdown attenuated imiquimod-induced psoriasis in mice, independently confirming the non-redundant requirement for IL-20RB signaling in keratinocyte-driven epidermal inflammation first observed in full knockouts.\",\n      \"evidence\": \"IL-20R2 knockdown mice, imiquimod psoriasis model, histology and western blot\",\n      \"pmids\": [\"31167692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown efficiency and residual IL-20RB activity not precisely quantified\", \"Relative contribution of macrophage vs. keratinocyte IL-20RB not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of Toxoplasma gondii ROP18 as an exogenous activator that co-opts IL-20RB to trigger host JAK/STAT3 signaling expanded the receptor's biology beyond endogenous cytokine signaling to pathogen exploitation.\",\n      \"evidence\": \"FRET, co-immunoprecipitation, STAT3 phosphorylation in IL-20RB-positive vs. IL-20RB-negative cell lines using CRISPR knockout parasites\",\n      \"pmids\": [\"32767999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance during Toxoplasma infection not demonstrated\", \"Binding site on IL-20RB for ROP18 not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that IL-19/IL-20RB signaling through JAK1/STAT3 in the bone metastatic niche drives lung cancer cell proliferation — suppressible by neutralizing anti-IL-20RB antibody — established a tumor-extrinsic paracrine loop and therapeutic vulnerability.\",\n      \"evidence\": \"IL-20RB overexpression/knockdown in lung cancer cells, in vivo bone metastasis model, neutralizing antibody, JAK1/STAT3 western blot\",\n      \"pmids\": [\"36006737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Patient-derived data on IL-20RB expression in bone metastases limited\", \"Contribution of IL-20 and IL-24 ligands to the same niche not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Photocaging of tyrosine 70 in IL-20R2 blocked IL-24 binding and signaling, with UV-mediated restoration proving that this single residue is a critical determinant of ligand–receptor complex assembly.\",\n      \"evidence\": \"Genetic code expansion with ortho-nitrobenzyl-tyrosine incorporation, biophysical binding and STAT phosphorylation assays\",\n      \"pmids\": [\"37484532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Y70 is equally important for IL-19 or IL-20 binding not tested\", \"Approach not validated in primary cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IL-20RB/STAT3 signaling was shown to promote cancer stemness and chemoresistance in pancreatic cancer, broadening the receptor's oncogenic roles beyond metastasis to treatment resistance.\",\n      \"evidence\": \"IL-20RB overexpression/knockdown in pancreatic cancer cells, spheroid formation, side-population analysis, in vivo tumor formation, STAT3 inhibitor rescue\",\n      \"pmids\": [\"38098005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of microenvironmental cells supplying IL-19 in pancreatic tumors not defined\", \"Whether other IL-20 subfamily members contribute equally not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that IL-20RB drives profibrotic M2-like macrophage polarization via JAK2/STAT3 and PI3K/Akt signaling extended its pathological roles to pulmonary fibrosis and identified JAK2 as an additional kinase partner beyond JAK1.\",\n      \"evidence\": \"Bleomycin-induced pulmonary fibrosis model, THP1 macrophage polarization, IL-20RB knockdown and neutralizing antibody, JAK2/STAT3 and PI3K/Akt western blot\",\n      \"pmids\": [\"38583686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAK2 directly associates with IL-20RB or with IL-20R1 not biochemically resolved\", \"Ligand identity driving macrophage IL-20RB signaling in fibrotic lung not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that TRIM21-mediated ubiquitin degradation of TAp63α derepresses IL-20RB transcription defined the first upstream regulatory axis controlling IL-20RB expression and linked it to PDAC metastasis.\",\n      \"evidence\": \"TRIM21/TAp63α overexpression/knockdown, promoter methylation analysis, ubiquitination assays, in vivo metastasis seeding in PDAC models\",\n      \"pmids\": [\"40460193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TAp63α binding to IL-20RB promoter not shown by ChIP\", \"Whether this regulatory axis operates in non-tumor tissues not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two IL-20RB-containing receptor complexes (type I and type II) differentially activate downstream transcriptional programs in specific cell types, and the structural basis of IL-19 recognition by IL-20RB, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of an IL-19-containing receptor complex\", \"Cell-type-specific signaling outputs of the two receptor complexes not systematically compared\", \"Role of alternative IL-20RB isoform in disease contexts unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 7, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"complexes\": [\n      \"IL-20R1/IL-20R2 type I receptor complex\",\n      \"IL-22R1/IL-20R2 type II receptor complex\"\n    ],\n    \"partners\": [\n      \"IL20R1\",\n      \"IL22R1\",\n      \"IL19\",\n      \"IL20\",\n      \"IL24\",\n      \"JAK1\",\n      \"STAT3\",\n      \"TRIM21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}