{"gene":"IL22RA1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2000,"finding":"IL-22 signals through a heterodimeric receptor complex composed of IL-22R (IL22RA1) and CRF2-4 (IL-10R2); IL-22 activates STATs 1, 3, and 5 through this receptor complex, and does not bind IL-10R alone.","method":"Cell-based signaling assays (STAT activation), receptor binding studies, cell line transfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — original discovery paper, multiple orthogonal methods (binding, signaling, cell-based), highly cited (440 citations)","pmids":["10875937"],"is_preprint":false},{"year":2004,"finding":"IL-22 binds IL-22R (IL22RA1) extracellular domain with measurable affinity but has undetectable affinity for IL-10R2 alone; IL-10R2 binds a surface created by the IL-22/IL-22R complex to further stabilize the ternary complex. Neutralizing antibodies and IL-22BP compete with IL-22R for overlapping epitopes on IL-22.","method":"ELISA-based binding assay using biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with defined receptor-Fc fusions and multiple orthogonal binding experiments","pmids":["15120653"],"is_preprint":false},{"year":2008,"finding":"Comprehensive mutagenesis identified specific IL-22 amino acid residues critical for binding to IL-22R (IL22RA1); the IL-22R and IL-10R2 binding sites are juxtaposed on adjacent surfaces of IL-22 contributed by helices A, D, F and loop AB. IL-22BP prevents IL-22R binding by occupying an overlapping epitope.","method":"Comprehensive mutagenesis combined with mammalian cell expression, ELISA, cell-based assays, and structural methods","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with structural and functional validation in a single rigorous study","pmids":["18675824"],"is_preprint":false},{"year":2018,"finding":"IL-22 promotes pancreatic cancer cell stemness via IL22RA1/STAT3 signaling; STAT3 is required for maintenance of the IL22RA1-high cancer cell population.","method":"Loss-of-function (siRNA/inhibitors), IL-22 stimulation assays, sphere formation assays, tumor xenograft experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/KO with defined cellular phenotype, multiple readouts; single lab","pmids":["29572224"],"is_preprint":false},{"year":2017,"finding":"IL-22R (IL22RA1) is the common receptor chain required for signaling by IL-20, IL-22, and IL-24; mice deficient in IL-22R display significant delay in wound healing, and IL-22 uniquely induces genes involved in reepithelialization, tissue remodeling, and innate host defense in wounded skin.","method":"Genetic knockout (IL-22R-deficient mice), wound healing assays, transcriptome analysis of wounded skin","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined phenotype plus transcriptomic mechanism; multiple cytokine comparisons","pmids":["28125663"],"is_preprint":false},{"year":2019,"finding":"IL-22Ra1 expression in lung epithelial cells is upregulated during influenza infection via TLR3 activation and subsequent IFNβ signaling through STAT1; induction of IL-22Ra1 increases IL-22 responsiveness (measured by pSTAT3 levels).","method":"qRT-PCR, western blot, immunofluorescence, STAT inhibitors, TLR3 inhibition, IFNAR2 neutralization; in vitro and in vivo H1N1 infection models","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple inhibitor approaches in both in vitro and in vivo models; single lab","pmids":["31416461"],"is_preprint":false},{"year":2024,"finding":"Intestinal epithelium-specific IL22RA1 signaling regulates systemic glucose metabolism and, in a microbiota-dependent manner, liver and white adipose tissue metabolism; transcription of intestinal lipid metabolism genes is regulated by IL-22 through IL22RA1, potentially involving IL-22-induced IL-18. Paneth cell-specific IL22RA1 signaling partially mediates systemic glucose metabolism after high-fat diet.","method":"Tissue-specific Il22ra1 knockout mice (intestinal epithelium, liver, WAT), high-fat diet model, transcriptomic analysis, microbiota analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple tissue-specific KO lines with defined metabolic phenotypes and mechanistic pathway placement","pmids":["38383607"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte-specific IL22RA1 deficiency causes diet-induced hepatic steatosis by enabling accumulation of oxysterol 3β-hydroxy-5-cholestenoic acid (3β HCA) via the ATF3/oxysterol 7α-hydroxylase axis; 3β HCA activates LXRα-driven lipogenesis, which is attenuated by IL-22 treatment.","method":"Hepatocyte-specific Il22ra1 knockout mice, metabolomics, primary hepatocyte cultures, human liver organoids, gene silencing (siRNA), oxysterol measurements","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO, organoid experiments, metabolomics, and mechanistic pathway validation with multiple orthogonal approaches","pmids":["38985984"],"is_preprint":false},{"year":2016,"finding":"IL-22 signaling through IL-22R in GVHD target organs activates STAT3 phosphorylation (downstream of IL-22R), promoting CD3+ T cell infiltration and tissue damage in murine acute graft versus host disease.","method":"In vivo murine allogeneic bone marrow transplantation model, IL-22 injection, western blot for p-STAT3, immunohistochemistry for CD3+ cells and IL-22R","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model with defined signaling readout; single lab","pmids":["27551984"],"is_preprint":false},{"year":2025,"finding":"Thymosin β4 released from mast cells impairs intestinal epithelial barrier by inhibiting the IL22RA1/JAK1/STAT3 signaling pathway, reducing tight junction proteins and the IL22RA1/Reg3γ cascade; this effect is mediated via CRH receptor 1 on mast cells.","method":"Tβ4-deficient rats, MC-deficient Kit(w-sh/w-sh) mice, wt peritoneal MC reconstitution, western blot, tight junction protein analysis, in vitro and in vivo stress models","journal":"World journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and reconstitution experiments with defined molecular pathway; single lab","pmids":["41278163"],"is_preprint":false},{"year":2025,"finding":"Blocking IL-22RA1 with the humanized monoclonal antibody temtokibart in 3D human skin equivalents and a mouse skin inflammation model inhibits IL-22/IL-22RA1 signaling, improves skin barrier integrity, reduces epidermal hyperplasia, normalizes lipid metabolism gene expression, and reduces local Cxcl1 and S100a9 expression.","method":"3D human skin equivalents, TPA mouse skin inflammation model, in situ hybridization, histology, molecular analysis; anti-IL-22RA1 antibody blockade","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo functional blockade with mechanistic molecular readouts; single lab","pmids":["41232574"],"is_preprint":false},{"year":2025,"finding":"Adipocyte-specific loss of IL-22RA1 signaling disrupts adipocyte differentiation and lipid metabolism in white adipose tissue during DSS-induced gut inflammation, leading to increased proliferation of preadipocytes/stromal cells without proper maturation, without affecting colonic inflammation levels.","method":"Adipocyte-specific Il22ra1 knockout mice, DSS-induced colitis model, HFD priming, gene expression analysis (Fabp4, Ki67), WAT histology","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, KO phenotype without full mechanistic pathway placement","pmids":[],"is_preprint":true}],"current_model":"IL22RA1 (IL-22R) is a transmembrane receptor subunit that binds IL-22 with high affinity on helices A, D, F and loop AB, recruits IL-10R2 to form a functional heterodimeric signaling complex, and activates JAK1/STAT3 (and STAT1/5) signaling in non-immune epithelial and parenchymal cells to regulate tissue barrier integrity, lipid and glucose metabolism, wound healing, and innate host defense; its expression is upregulated by IFNβ/STAT1 during viral infection, and tissue-specific IL22RA1 signaling in intestinal epithelium, hepatocytes, and adipocytes controls distinct aspects of metabolic and inflammatory homeostasis."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of IL22RA1 as the ligand-binding chain of a heterodimeric receptor with IL-10R2 established the molecular basis for IL-22 signal transduction through STAT1, STAT3, and STAT5.","evidence":"Cell-based STAT activation assays, receptor binding studies, and cell line transfection","pmids":["10875937"],"confidence":"High","gaps":["Structural details of the IL-22/IL22RA1 interface unknown","Downstream transcriptional targets not defined","In vivo physiological roles not established"]},{"year":2004,"claim":"Sequential binding studies demonstrated that IL-22 binds IL22RA1 first with measurable affinity, while IL-10R2 binds only the preformed IL-22/IL22RA1 binary complex, establishing the ordered assembly mechanism of the ternary signaling complex.","evidence":"ELISA-based binding assays with receptor-Fc fusion proteins and sequential addition experiments","pmids":["15120653"],"confidence":"High","gaps":["Atomic-resolution structure of the ternary complex not determined","Kinetic binding parameters (SPR) not reported","Mechanism by which IL-22BP outcompetes IL22RA1 not fully defined"]},{"year":2008,"claim":"Comprehensive mutagenesis mapped the IL22RA1-binding surface on IL-22 to helices A, D, F and loop AB, and showed the IL-10R2 binding site is juxtaposed on an adjacent surface, resolving how a single cytokine engages two receptor chains and how IL-22BP blocks signaling.","evidence":"Systematic mutagenesis with mammalian cell expression, ELISA, cell-based functional assays, and structural analysis","pmids":["18675824"],"confidence":"High","gaps":["Crystal structure of the full ternary complex not solved","Conformational changes upon receptor engagement not characterized","Residues on IL22RA1 contributing to binding not mapped"]},{"year":2016,"claim":"Demonstration that IL-22/IL22RA1 signaling activates STAT3 phosphorylation in GVHD target organs established that this pathway contributes to immunopathology beyond its epithelial-protective roles.","evidence":"Murine allogeneic bone marrow transplantation model with IL-22 injection, p-STAT3 western blot, IHC","pmids":["27551984"],"confidence":"Medium","gaps":["Direct versus indirect role of IL-22R signaling in T cell infiltration not resolved","Cell-type-specific contributions in target organs not dissected","Context-dependent switch between protective and pathogenic signaling unclear"]},{"year":2017,"claim":"Genetic ablation of IL22RA1 in mice revealed its non-redundant requirement for wound healing and identified IL-22-driven transcriptional programs in reepithelialization, tissue remodeling, and innate defense, establishing IL22RA1 as a shared receptor for IL-20, IL-22, and IL-24 with distinct downstream gene signatures.","evidence":"IL-22R-deficient mice, wound healing assays, transcriptome analysis of wounded skin","pmids":["28125663"],"confidence":"High","gaps":["Relative contribution of IL-20, IL-22, and IL-24 to wound phenotype not deconvolved","Signaling intermediates downstream of STAT3 in wound repair not defined","Human relevance of wound healing delay not tested"]},{"year":2018,"claim":"IL-22/IL22RA1/STAT3 signaling was shown to promote cancer cell stemness in pancreatic cancer, revealing a pathological co-option of this epithelial signaling axis.","evidence":"siRNA/inhibitor loss-of-function, sphere formation assays, tumor xenograft experiments","pmids":["29572224"],"confidence":"Medium","gaps":["Source of IL-22 in the tumor microenvironment not identified","STAT3 target genes mediating stemness not fully characterized","Generalizability to other IL22RA1-expressing cancers unknown"]},{"year":2019,"claim":"Discovery that IL22RA1 expression is upregulated by TLR3-IFNβ-STAT1 signaling during influenza infection demonstrated a feedforward mechanism that amplifies IL-22 responsiveness in lung epithelium during viral challenge.","evidence":"qRT-PCR, western blot, STAT/TLR3 inhibitors, IFNAR2 neutralization in vitro and in H1N1 infection models","pmids":["31416461"],"confidence":"Medium","gaps":["Transcription factors directly binding the IL22RA1 promoter not identified","Whether other viral infections induce IL22RA1 similarly not tested","Functional consequence for lung barrier protection not directly measured"]},{"year":2024,"claim":"Tissue-specific knockouts revealed that intestinal epithelial IL22RA1 controls systemic glucose metabolism and microbiota-dependent liver and adipose lipid metabolism, while hepatocyte IL22RA1 prevents steatosis by suppressing oxysterol (3β HCA)-driven LXRα lipogenesis through the ATF3/CYP7B1 axis, establishing organ-specific metabolic functions for a single receptor.","evidence":"Multiple tissue-specific Il22ra1 knockout mice, high-fat diet models, metabolomics, primary hepatocyte cultures, human liver organoids, gene silencing","pmids":["38383607","38985984"],"confidence":"High","gaps":["Direct STAT3 targets mediating metabolic gene regulation in each tissue not mapped genome-wide","How IL-22-induced IL-18 mediates intestinal lipid metabolism not mechanistically resolved","Integration with insulin and other metabolic signaling pathways not defined"]},{"year":2025,"claim":"Functional blockade and genetic studies confirmed that IL22RA1/JAK1/STAT3 signaling maintains epithelial barrier integrity through tight junction proteins and the Reg3γ antimicrobial cascade, and that therapeutic antibody blockade of IL22RA1 normalizes skin hyperplasia and lipid metabolism in inflammatory settings.","evidence":"Tβ4-deficient rats, MC-deficient mice with reconstitution, anti-IL-22RA1 antibody (temtokibart) in 3D human skin equivalents and mouse skin inflammation model","pmids":["41278163","41232574"],"confidence":"Medium","gaps":["Mechanism by which thymosin β4 inhibits IL22RA1 signaling not fully elucidated","Long-term consequences of IL22RA1 blockade on barrier immunity not assessed","Whether temtokibart effects extend beyond skin to other IL22RA1-expressing tissues not tested"]},{"year":null,"claim":"A high-resolution crystal structure of the complete IL-22/IL22RA1/IL-10R2 ternary complex is still lacking, and the mechanism by which IL22RA1 couples to JAK1 versus other downstream kinases in a tissue-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution ternary complex structure available","Tissue-specific signaling selectivity (STAT3 vs STAT1 vs STAT5) mechanism unknown","Transcription factor network directly downstream of STAT3 in each tissue not comprehensively defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,5,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,7]}],"complexes":["IL-22R/IL-10R2 heterodimeric receptor complex"],"partners":["IL10RB","IL22","JAK1","STAT3","IL22RA2"],"other_free_text":[]},"mechanistic_narrative":"IL22RA1 is a type I transmembrane receptor subunit that serves as the ligand-binding chain for IL-22 (and also IL-20 and IL-24), forming a heterodimeric signaling complex with IL-10R2 to activate JAK1/STAT3 (and STAT1/STAT5) pathways in non-immune epithelial and parenchymal cells, thereby governing tissue barrier integrity, wound healing, innate host defense, and lipid and glucose metabolism [PMID:10875937, PMID:28125663, PMID:38383607]. IL-22 binds IL22RA1 with high affinity through surfaces on helices A, D, F and loop AB, creating a composite interface that subsequently recruits IL-10R2 into a ternary signaling complex; IL-22BP and neutralizing antibodies compete with IL22RA1 for overlapping epitopes on IL-22 [PMID:15120653, PMID:18675824]. Tissue-specific IL22RA1 signaling in intestinal epithelium controls systemic glucose metabolism and microbiota-dependent hepatic lipid handling, while hepatocyte-specific IL22RA1 prevents diet-induced steatosis by suppressing oxysterol-driven LXRα lipogenesis through the ATF3/oxysterol 7α-hydroxylase axis [PMID:38383607, PMID:38985984]. IL22RA1 expression is dynamically regulated, being upregulated by IFNβ/STAT1 during viral infection to amplify IL-22 responsiveness, and its downstream STAT3 signaling in skin and intestinal epithelium maintains tight junction proteins and antimicrobial peptide cascades including Reg3γ [PMID:31416461, PMID:41278163]."},"prefetch_data":{"uniprot":{"accession":"Q8N6P7","full_name":"Interleukin-22 receptor subunit alpha-1","aliases":["Cytokine receptor class-II member 9","Cytokine receptor family 2 member 9","CRF2-9","ZcytoR11"],"length_aa":574,"mass_kda":63.1,"function":"Component of the receptor for IL20, IL22 and IL24. Component of IL22 receptor formed by IL22RA1 and IL10RB enabling IL22 signaling via JAK/STAT pathways. IL22 also induces activation of MAPK1/MAPK3 and Akt kinases pathways. Component of one of the receptor for IL20 and IL24 formed by IL22RA1 and IL20RB also signaling through STATs activation. Mediates IL24 antiangiogenic activity as well as IL24 inhibitory effect on endothelial cell tube formation and differentiation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N6P7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL22RA1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL22RA1","total_profiled":1310},"omim":[{"mim_id":"606464","title":"HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP","url":"https://www.omim.org/entry/606464"},{"mim_id":"605679","title":"INTERLEUKIN 26; IL26","url":"https://www.omim.org/entry/605679"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":189.0}],"url":"https://www.proteinatlas.org/search/IL22RA1"},"hgnc":{"alias_symbol":["CRF2-9"],"prev_symbol":["IL22R"]},"alphafold":{"accession":"Q8N6P7","domains":[{"cath_id":"2.60.40.10","chopping":"26-119","consensus_level":"high","plddt":93.9754,"start":26,"end":119},{"cath_id":"2.60.40.10","chopping":"127-227","consensus_level":"high","plddt":94.2632,"start":127,"end":227}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6P7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6P7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6P7-F1-predicted_aligned_error_v6.png","plddt_mean":61.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL22RA1","jax_strain_url":"https://www.jax.org/strain/search?query=IL22RA1"},"sequence":{"accession":"Q8N6P7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6P7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6P7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6P7"}},"corpus_meta":[{"pmid":"10875937","id":"PMC_10875937","title":"Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10875937","citation_count":440,"is_preprint":false},{"pmid":"29572224","id":"PMC_29572224","title":"IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29572224","citation_count":93,"is_preprint":false},{"pmid":"28125663","id":"PMC_28125663","title":"IL-22R Ligands IL-20, IL-22, and IL-24 Promote Wound Healing in Diabetic db/db Mice.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28125663","citation_count":73,"is_preprint":false},{"pmid":"15120653","id":"PMC_15120653","title":"Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2.","date":"2004","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15120653","citation_count":57,"is_preprint":false},{"pmid":"18675824","id":"PMC_18675824","title":"IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18675824","citation_count":51,"is_preprint":false},{"pmid":"31391457","id":"PMC_31391457","title":"LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenon's capsule fibroblasts.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31391457","citation_count":29,"is_preprint":false},{"pmid":"38383607","id":"PMC_38383607","title":"Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38383607","citation_count":24,"is_preprint":false},{"pmid":"30816520","id":"PMC_30816520","title":"IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30816520","citation_count":15,"is_preprint":false},{"pmid":"23058849","id":"PMC_23058849","title":"Expression of IL-22, IL-22R and IL-23 in the peri-implant soft tissues of patients with peri-implantitis.","date":"2012","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/23058849","citation_count":15,"is_preprint":false},{"pmid":"35874683","id":"PMC_35874683","title":"IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35874683","citation_count":12,"is_preprint":false},{"pmid":"31416461","id":"PMC_31416461","title":"IL-22Ra1 is induced during influenza infection by direct and indirect TLR3 induction of STAT1.","date":"2019","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/31416461","citation_count":12,"is_preprint":false},{"pmid":"38375746","id":"PMC_38375746","title":"Limonin alleviates high-fat diet-induced dyslipidemia by regulating the intestinal barrier via the microbiota-related ILC3-IL22-IL22R pathway.","date":"2024","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/38375746","citation_count":10,"is_preprint":false},{"pmid":"33878363","id":"PMC_33878363","title":"Specific bioactivity of IL-22 in intestinal cells as revealed by the expression of IL-22RA1 in Mandarin fish, Siniperca chuatsi.","date":"2021","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33878363","citation_count":9,"is_preprint":false},{"pmid":"27551984","id":"PMC_27551984","title":"IL-22 promoted CD3+ T cell infiltration by IL-22R induced STAT3 phosphorylation in murine acute graft versus host disease target organs after allogeneic bone marrow transplantation.","date":"2016","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27551984","citation_count":9,"is_preprint":false},{"pmid":"38985984","id":"PMC_38985984","title":"Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver.","date":"2024","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38985984","citation_count":8,"is_preprint":false},{"pmid":"38081403","id":"PMC_38081403","title":"Evolutionarily conserved IL-22 participates in gut mucosal barrier through its receptors IL-22BP, IL-10R2 and IL-22RA1 during bacterial infection in teleost.","date":"2023","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38081403","citation_count":8,"is_preprint":false},{"pmid":"35154603","id":"PMC_35154603","title":"Association of IL-22 and IL-22RA1 gene variants in Iranian patients with colorectal cancer.","date":"2021","source":"Gastroenterology and hepatology from bed to bench","url":"https://pubmed.ncbi.nlm.nih.gov/35154603","citation_count":4,"is_preprint":false},{"pmid":"41232574","id":"PMC_41232574","title":"Neutralizing IL-22RA1 improves histologic and molecular alterations associated with atopic dermatitis pathogenesis.","date":"2025","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41232574","citation_count":1,"is_preprint":false},{"pmid":"40775324","id":"PMC_40775324","title":"Evaluating IL22RA1 expression as a predictive indicator in human colon cancer progression.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40775324","citation_count":0,"is_preprint":false},{"pmid":"35838587","id":"PMC_35838587","title":"Lack of Association of Polymorphisms in IL22 and IL22RA1 Genes with Fibrosis Severity in Patients with Chronic Hepatitis C.","date":"2022","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35838587","citation_count":0,"is_preprint":false},{"pmid":"41278163","id":"PMC_41278163","title":"Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome.","date":"2025","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/41278163","citation_count":0,"is_preprint":false},{"pmid":"41467542","id":"PMC_41467542","title":"Low-Temperature Fabrication of Thymosin β4-Loaded Soluble Microneedles to Promote Wound Healing by Specific Binding to Downregulated Immune Regulators Vsig4 and IL22rɑ2.","date":"2025","source":"Advanced healthcare materials","url":"https://pubmed.ncbi.nlm.nih.gov/41467542","citation_count":0,"is_preprint":false},{"pmid":"41232575","id":"PMC_41232575","title":"Targeting IL-22RA1 with temtokibart: A novel approach in atopic dermatitis: Phase 2a monotherapy study results.","date":"2025","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41232575","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.18.624144","title":"Activation of IL1A/IRAK1 axis and downstream proinflammatory signaling in healthy adult and neonatal African American skin","date":"2024-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.18.624144","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.14.688505","title":"Adipocyte IL-22RA1 signaling promotes structural and functional remodeling of white adipose tissue following acute intestinal damage","date":"2025-11-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688505","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14677,"output_tokens":2845,"usd":0.043353},"stage2":{"model":"claude-opus-4-6","input_tokens":6220,"output_tokens":2854,"usd":0.153675},"total_usd":0.197028,"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\": 2000,\n      \"finding\": \"IL-22 signals through a heterodimeric receptor complex composed of IL-22R (IL22RA1) and CRF2-4 (IL-10R2); IL-22 activates STATs 1, 3, and 5 through this receptor complex, and does not bind IL-10R alone.\",\n      \"method\": \"Cell-based signaling assays (STAT activation), receptor binding studies, cell line transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper, multiple orthogonal methods (binding, signaling, cell-based), highly cited (440 citations)\",\n      \"pmids\": [\"10875937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-22 binds IL-22R (IL22RA1) extracellular domain with measurable affinity but has undetectable affinity for IL-10R2 alone; IL-10R2 binds a surface created by the IL-22/IL-22R complex to further stabilize the ternary complex. Neutralizing antibodies and IL-22BP compete with IL-22R for overlapping epitopes on IL-22.\",\n      \"method\": \"ELISA-based binding assay using biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with defined receptor-Fc fusions and multiple orthogonal binding experiments\",\n      \"pmids\": [\"15120653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Comprehensive mutagenesis identified specific IL-22 amino acid residues critical for binding to IL-22R (IL22RA1); the IL-22R and IL-10R2 binding sites are juxtaposed on adjacent surfaces of IL-22 contributed by helices A, D, F and loop AB. IL-22BP prevents IL-22R binding by occupying an overlapping epitope.\",\n      \"method\": \"Comprehensive mutagenesis combined with mammalian cell expression, ELISA, cell-based assays, and structural methods\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with structural and functional validation in a single rigorous study\",\n      \"pmids\": [\"18675824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-22 promotes pancreatic cancer cell stemness via IL22RA1/STAT3 signaling; STAT3 is required for maintenance of the IL22RA1-high cancer cell population.\",\n      \"method\": \"Loss-of-function (siRNA/inhibitors), IL-22 stimulation assays, sphere formation assays, tumor xenograft experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/KO with defined cellular phenotype, multiple readouts; single lab\",\n      \"pmids\": [\"29572224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-22R (IL22RA1) is the common receptor chain required for signaling by IL-20, IL-22, and IL-24; mice deficient in IL-22R display significant delay in wound healing, and IL-22 uniquely induces genes involved in reepithelialization, tissue remodeling, and innate host defense in wounded skin.\",\n      \"method\": \"Genetic knockout (IL-22R-deficient mice), wound healing assays, transcriptome analysis of wounded skin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotype plus transcriptomic mechanism; multiple cytokine comparisons\",\n      \"pmids\": [\"28125663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-22Ra1 expression in lung epithelial cells is upregulated during influenza infection via TLR3 activation and subsequent IFNβ signaling through STAT1; induction of IL-22Ra1 increases IL-22 responsiveness (measured by pSTAT3 levels).\",\n      \"method\": \"qRT-PCR, western blot, immunofluorescence, STAT inhibitors, TLR3 inhibition, IFNAR2 neutralization; in vitro and in vivo H1N1 infection models\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple inhibitor approaches in both in vitro and in vivo models; single lab\",\n      \"pmids\": [\"31416461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Intestinal epithelium-specific IL22RA1 signaling regulates systemic glucose metabolism and, in a microbiota-dependent manner, liver and white adipose tissue metabolism; transcription of intestinal lipid metabolism genes is regulated by IL-22 through IL22RA1, potentially involving IL-22-induced IL-18. Paneth cell-specific IL22RA1 signaling partially mediates systemic glucose metabolism after high-fat diet.\",\n      \"method\": \"Tissue-specific Il22ra1 knockout mice (intestinal epithelium, liver, WAT), high-fat diet model, transcriptomic analysis, microbiota analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple tissue-specific KO lines with defined metabolic phenotypes and mechanistic pathway placement\",\n      \"pmids\": [\"38383607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte-specific IL22RA1 deficiency causes diet-induced hepatic steatosis by enabling accumulation of oxysterol 3β-hydroxy-5-cholestenoic acid (3β HCA) via the ATF3/oxysterol 7α-hydroxylase axis; 3β HCA activates LXRα-driven lipogenesis, which is attenuated by IL-22 treatment.\",\n      \"method\": \"Hepatocyte-specific Il22ra1 knockout mice, metabolomics, primary hepatocyte cultures, human liver organoids, gene silencing (siRNA), oxysterol measurements\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO, organoid experiments, metabolomics, and mechanistic pathway validation with multiple orthogonal approaches\",\n      \"pmids\": [\"38985984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-22 signaling through IL-22R in GVHD target organs activates STAT3 phosphorylation (downstream of IL-22R), promoting CD3+ T cell infiltration and tissue damage in murine acute graft versus host disease.\",\n      \"method\": \"In vivo murine allogeneic bone marrow transplantation model, IL-22 injection, western blot for p-STAT3, immunohistochemistry for CD3+ cells and IL-22R\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with defined signaling readout; single lab\",\n      \"pmids\": [\"27551984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Thymosin β4 released from mast cells impairs intestinal epithelial barrier by inhibiting the IL22RA1/JAK1/STAT3 signaling pathway, reducing tight junction proteins and the IL22RA1/Reg3γ cascade; this effect is mediated via CRH receptor 1 on mast cells.\",\n      \"method\": \"Tβ4-deficient rats, MC-deficient Kit(w-sh/w-sh) mice, wt peritoneal MC reconstitution, western blot, tight junction protein analysis, in vitro and in vivo stress models\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and reconstitution experiments with defined molecular pathway; single lab\",\n      \"pmids\": [\"41278163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Blocking IL-22RA1 with the humanized monoclonal antibody temtokibart in 3D human skin equivalents and a mouse skin inflammation model inhibits IL-22/IL-22RA1 signaling, improves skin barrier integrity, reduces epidermal hyperplasia, normalizes lipid metabolism gene expression, and reduces local Cxcl1 and S100a9 expression.\",\n      \"method\": \"3D human skin equivalents, TPA mouse skin inflammation model, in situ hybridization, histology, molecular analysis; anti-IL-22RA1 antibody blockade\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional blockade with mechanistic molecular readouts; single lab\",\n      \"pmids\": [\"41232574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Adipocyte-specific loss of IL-22RA1 signaling disrupts adipocyte differentiation and lipid metabolism in white adipose tissue during DSS-induced gut inflammation, leading to increased proliferation of preadipocytes/stromal cells without proper maturation, without affecting colonic inflammation levels.\",\n      \"method\": \"Adipocyte-specific Il22ra1 knockout mice, DSS-induced colitis model, HFD priming, gene expression analysis (Fabp4, Ki67), WAT histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, KO phenotype without full mechanistic pathway placement\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL22RA1 (IL-22R) is a transmembrane receptor subunit that binds IL-22 with high affinity on helices A, D, F and loop AB, recruits IL-10R2 to form a functional heterodimeric signaling complex, and activates JAK1/STAT3 (and STAT1/5) signaling in non-immune epithelial and parenchymal cells to regulate tissue barrier integrity, lipid and glucose metabolism, wound healing, and innate host defense; its expression is upregulated by IFNβ/STAT1 during viral infection, and tissue-specific IL22RA1 signaling in intestinal epithelium, hepatocytes, and adipocytes controls distinct aspects of metabolic and inflammatory homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL22RA1 is a type I transmembrane receptor subunit that serves as the ligand-binding chain for IL-22 (and also IL-20 and IL-24), forming a heterodimeric signaling complex with IL-10R2 to activate JAK1/STAT3 (and STAT1/STAT5) pathways in non-immune epithelial and parenchymal cells, thereby governing tissue barrier integrity, wound healing, innate host defense, and lipid and glucose metabolism [PMID:10875937, PMID:28125663, PMID:38383607]. IL-22 binds IL22RA1 with high affinity through surfaces on helices A, D, F and loop AB, creating a composite interface that subsequently recruits IL-10R2 into a ternary signaling complex; IL-22BP and neutralizing antibodies compete with IL22RA1 for overlapping epitopes on IL-22 [PMID:15120653, PMID:18675824]. Tissue-specific IL22RA1 signaling in intestinal epithelium controls systemic glucose metabolism and microbiota-dependent hepatic lipid handling, while hepatocyte-specific IL22RA1 prevents diet-induced steatosis by suppressing oxysterol-driven LXRα lipogenesis through the ATF3/oxysterol 7α-hydroxylase axis [PMID:38383607, PMID:38985984]. IL22RA1 expression is dynamically regulated, being upregulated by IFNβ/STAT1 during viral infection to amplify IL-22 responsiveness, and its downstream STAT3 signaling in skin and intestinal epithelium maintains tight junction proteins and antimicrobial peptide cascades including Reg3γ [PMID:31416461, PMID:41278163].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of IL22RA1 as the ligand-binding chain of a heterodimeric receptor with IL-10R2 established the molecular basis for IL-22 signal transduction through STAT1, STAT3, and STAT5.\",\n      \"evidence\": \"Cell-based STAT activation assays, receptor binding studies, and cell line transfection\",\n      \"pmids\": [\"10875937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural details of the IL-22/IL22RA1 interface unknown\",\n        \"Downstream transcriptional targets not defined\",\n        \"In vivo physiological roles not established\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Sequential binding studies demonstrated that IL-22 binds IL22RA1 first with measurable affinity, while IL-10R2 binds only the preformed IL-22/IL22RA1 binary complex, establishing the ordered assembly mechanism of the ternary signaling complex.\",\n      \"evidence\": \"ELISA-based binding assays with receptor-Fc fusion proteins and sequential addition experiments\",\n      \"pmids\": [\"15120653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the ternary complex not determined\",\n        \"Kinetic binding parameters (SPR) not reported\",\n        \"Mechanism by which IL-22BP outcompetes IL22RA1 not fully defined\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Comprehensive mutagenesis mapped the IL22RA1-binding surface on IL-22 to helices A, D, F and loop AB, and showed the IL-10R2 binding site is juxtaposed on an adjacent surface, resolving how a single cytokine engages two receptor chains and how IL-22BP blocks signaling.\",\n      \"evidence\": \"Systematic mutagenesis with mammalian cell expression, ELISA, cell-based functional assays, and structural analysis\",\n      \"pmids\": [\"18675824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal structure of the full ternary complex not solved\",\n        \"Conformational changes upon receptor engagement not characterized\",\n        \"Residues on IL22RA1 contributing to binding not mapped\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that IL-22/IL22RA1 signaling activates STAT3 phosphorylation in GVHD target organs established that this pathway contributes to immunopathology beyond its epithelial-protective roles.\",\n      \"evidence\": \"Murine allogeneic bone marrow transplantation model with IL-22 injection, p-STAT3 western blot, IHC\",\n      \"pmids\": [\"27551984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect role of IL-22R signaling in T cell infiltration not resolved\",\n        \"Cell-type-specific contributions in target organs not dissected\",\n        \"Context-dependent switch between protective and pathogenic signaling unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic ablation of IL22RA1 in mice revealed its non-redundant requirement for wound healing and identified IL-22-driven transcriptional programs in reepithelialization, tissue remodeling, and innate defense, establishing IL22RA1 as a shared receptor for IL-20, IL-22, and IL-24 with distinct downstream gene signatures.\",\n      \"evidence\": \"IL-22R-deficient mice, wound healing assays, transcriptome analysis of wounded skin\",\n      \"pmids\": [\"28125663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of IL-20, IL-22, and IL-24 to wound phenotype not deconvolved\",\n        \"Signaling intermediates downstream of STAT3 in wound repair not defined\",\n        \"Human relevance of wound healing delay not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"IL-22/IL22RA1/STAT3 signaling was shown to promote cancer cell stemness in pancreatic cancer, revealing a pathological co-option of this epithelial signaling axis.\",\n      \"evidence\": \"siRNA/inhibitor loss-of-function, sphere formation assays, tumor xenograft experiments\",\n      \"pmids\": [\"29572224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Source of IL-22 in the tumor microenvironment not identified\",\n        \"STAT3 target genes mediating stemness not fully characterized\",\n        \"Generalizability to other IL22RA1-expressing cancers unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that IL22RA1 expression is upregulated by TLR3-IFNβ-STAT1 signaling during influenza infection demonstrated a feedforward mechanism that amplifies IL-22 responsiveness in lung epithelium during viral challenge.\",\n      \"evidence\": \"qRT-PCR, western blot, STAT/TLR3 inhibitors, IFNAR2 neutralization in vitro and in H1N1 infection models\",\n      \"pmids\": [\"31416461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcription factors directly binding the IL22RA1 promoter not identified\",\n        \"Whether other viral infections induce IL22RA1 similarly not tested\",\n        \"Functional consequence for lung barrier protection not directly measured\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tissue-specific knockouts revealed that intestinal epithelial IL22RA1 controls systemic glucose metabolism and microbiota-dependent liver and adipose lipid metabolism, while hepatocyte IL22RA1 prevents steatosis by suppressing oxysterol (3β HCA)-driven LXRα lipogenesis through the ATF3/CYP7B1 axis, establishing organ-specific metabolic functions for a single receptor.\",\n      \"evidence\": \"Multiple tissue-specific Il22ra1 knockout mice, high-fat diet models, metabolomics, primary hepatocyte cultures, human liver organoids, gene silencing\",\n      \"pmids\": [\"38383607\", \"38985984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct STAT3 targets mediating metabolic gene regulation in each tissue not mapped genome-wide\",\n        \"How IL-22-induced IL-18 mediates intestinal lipid metabolism not mechanistically resolved\",\n        \"Integration with insulin and other metabolic signaling pathways not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Functional blockade and genetic studies confirmed that IL22RA1/JAK1/STAT3 signaling maintains epithelial barrier integrity through tight junction proteins and the Reg3γ antimicrobial cascade, and that therapeutic antibody blockade of IL22RA1 normalizes skin hyperplasia and lipid metabolism in inflammatory settings.\",\n      \"evidence\": \"Tβ4-deficient rats, MC-deficient mice with reconstitution, anti-IL-22RA1 antibody (temtokibart) in 3D human skin equivalents and mouse skin inflammation model\",\n      \"pmids\": [\"41278163\", \"41232574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which thymosin β4 inhibits IL22RA1 signaling not fully elucidated\",\n        \"Long-term consequences of IL22RA1 blockade on barrier immunity not assessed\",\n        \"Whether temtokibart effects extend beyond skin to other IL22RA1-expressing tissues not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution crystal structure of the complete IL-22/IL22RA1/IL-10R2 ternary complex is still lacking, and the mechanism by which IL22RA1 couples to JAK1 versus other downstream kinases in a tissue-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No atomic-resolution ternary complex structure available\",\n        \"Tissue-specific signaling selectivity (STAT3 vs STAT1 vs STAT5) mechanism unknown\",\n        \"Transcription factor network directly downstream of STAT3 in each tissue not comprehensively defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 3, 5, 8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 5, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"IL-22R/IL-10R2 heterodimeric receptor complex\"\n    ],\n    \"partners\": [\n      \"IL10RB\",\n      \"IL22\",\n      \"JAK1\",\n      \"STAT3\",\n      \"IL22RA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}