{"gene":"IL17RB","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2001,"finding":"IL-17RB (IL-17Rh1/EVI27) was identified as a receptor for the cytokine IL-17E (IL-25), and this interaction induces NF-κB activation and IL-8 production.","method":"Ligand-receptor binding assay, NF-κB reporter assay, IL-8 ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — original receptor-ligand identification with functional signaling readouts, foundational paper","pmids":["11058597"],"is_preprint":false},{"year":2000,"finding":"IL-17RB (EVI27) encodes a novel transmembrane protein with homology to the IL-17 receptor; multiple isoforms exist including secreted soluble forms produced by intron incorporation or proteolytic cleavage, and it is expressed on selected T-cell, B-cell and myeloid cell lines.","method":"Molecular cloning, Northern blot, Western blot, isoform characterization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular and biochemical characterization of protein structure and expression, single lab","pmids":["10815801"],"is_preprint":false},{"year":2008,"finding":"IL-25-mediated biological activities (including IL-5/IL-13 production and pulmonary inflammation) require both IL-17RB and IL-17RA as a heteromeric receptor complex; neither subunit alone is sufficient.","method":"Knockout mice (IL-17RB KO and IL-17RA KO), antagonistic monoclonal antibodies, in vitro splenocyte cytokine assay, in vivo intranasal IL-25 model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and antibody blockade with multiple orthogonal in vitro and in vivo readouts, strong mechanistic evidence","pmids":["18768888"],"is_preprint":false},{"year":2009,"finding":"IL-17RB is highly expressed on a subset of CD4+ invariant NKT (iNKT) cells but not on activated conventional T cells; IL-17RB+ iNKT cells produce large amounts of Th2 cytokines upon IL-25 stimulation and are necessary and sufficient to restore airway hyperreactivity (AHR) in iNKT-deficient mice.","method":"Flow cytometry, adoptive transfer into iNKT-deficient mice, intranasal IL-25 AHR model, cytokine assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct localization by FACS, functional reconstitution by adoptive transfer with defined phenotypic readout","pmids":["19342692"],"is_preprint":false},{"year":2009,"finding":"IL-17RB (IL-25R) is expressed on IL-4-producing CD11b+GR1+ myeloid cells in the lung and bone marrow during chronic allergen challenge; SCF-stimulated c-kit+ eosinophils produce IL-25, and Th2 cytokine production from IL-17RB+ myeloid cells is dependent on SCF.","method":"Cell sorting, 4get reporter mice, flow cytometry, anti-SCF neutralization, cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct identification of IL-17RB-expressing cell type with functional consequence, single lab","pmids":["19828636"],"is_preprint":false},{"year":2010,"finding":"IL-17RB is expressed on basophils; IL-3 upregulates IL-17RB mRNA and protein on basophils; IL-25 activation of IL-17RB inhibits basophil apoptosis and enhances IgE-mediated degranulation.","method":"Flow cytometry, qRT-PCR, apoptosis assay (Annexin-V), beta-hexosaminidase degranulation assay, ELISA","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional characterization of IL-17RB on basophils with multiple assays, single lab","pmids":["20545698"],"is_preprint":false},{"year":2012,"finding":"IL-25 promotes basic fibroblast growth factor (bFGF) expression and angiogenesis in human endothelial cells through IL-17RB but not IL-17RA, via a PI3K-dependent signaling pathway.","method":"Receptor-blocking antibodies, siRNA knockdown, PI3K inhibitor (LY294002), ELISA, in vitro angiogenesis assay, PCR","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-specific blockade plus signaling pathway inhibitor with functional angiogenesis readout, single lab","pmids":["23106660"],"is_preprint":false},{"year":2013,"finding":"COX-2-derived prostaglandins PGD2 and PGE2 suppress Th9 cell differentiation by downregulating IL-17RB expression via a protein kinase A-dependent mechanism.","method":"COX-2 KO mice, synthetic prostaglandins, selective inhibitors, siRNA, flow cytometry, real-time PCR, immunoblotting","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO and pharmacologic approaches with PKA pathway identified, single lab","pmids":["23449692"],"is_preprint":false},{"year":2014,"finding":"IL-17RB is aberrantly overexpressed in HTLV-1 immortalized T cells; Tax induces IL-17RB expression in an IKK/NF-κB-dependent manner; IL-17RB is required for Tax-induced canonical NF-κB activation, HTLV-1-induced immortalization of primary T cells, and survival of HTLV-1 transformed cells via an IL-9-dependent autocrine loop.","method":"RNA sequencing, siRNA knockdown, NF-κB reporter assay, T-cell immortalization assay, cytokine measurement, ATL patient sample analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including KD, reporter assay, primary cell transformation, and patient data demonstrating pathway placement","pmids":["25340344"],"is_preprint":false},{"year":2014,"finding":"IL-25 (IL-17E) and IL-17RB promote immunopathology during RSV infection; IL-17RB-/- mice show decreased Th2 and increased Th17 cytokine production along with reduced lung inflammation during RSV infection and RSV-driven asthma exacerbation.","method":"IL-17RB knockout mice, RSV infection model, neutralizing antibodies, cytokine measurement, AHR assay","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined inflammatory phenotype, single lab","pmids":["24407884"],"is_preprint":false},{"year":2017,"finding":"TGF-β1 secreted by Tregs in tumor-draining lymph nodes upregulates IL-17RB in breast tumor cells via Smad2/3/4 signaling, and IL-17RB upregulation contributes to increased tumor malignancy and distant metastasis.","method":"Syngeneic mouse mammary tumor model, TGF-β1 neutralization, Treg depletion, Smad pathway inhibition, xenograft tumor assay, clinical sample analysis","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model with multiple interventions and defined downstream signaling pathway, single lab","pmids":["28993429"],"is_preprint":false},{"year":2017,"finding":"IL-17B activates IL-17RB in thyroid cancer cells to promote invasion and metastasis via ERK1/2 pathway-mediated MMP-9 upregulation; knockdown of IL-17RB attenuates IL-17B-induced invasion, and ERK1/2 inhibition blocks MMP-9 expression and invasion.","method":"IL-17RB knockdown, in vitro invasion/migration assays, in vivo xenograft, Western blot, ERK1/2 inhibitor","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KD and pathway inhibitor with both in vitro and in vivo functional readouts, single lab","pmids":["28715683"],"is_preprint":false},{"year":2019,"finding":"IL-17RB marks intestinal tumor stem cells (TSCs) in mouse intestinal adenomas in an IL-13-dependent manner, and marks cancer stem cells (CSCs) in a subset of human colorectal cancers (hCRCs) that expand independently of IL-13; long-term ablation of IL-17RB-expressing CSCs strongly suppresses tumor growth in vivo.","method":"Il17rb-CreERT2 lineage-tracing mice, CRISPR-Cas9 IL17RB-CreERT2 knockin organoids, xenograft tumors, in vivo cell ablation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic lineage tracing in mice and human organoids with xenograft in vivo validation, multiple orthogonal methods","pmids":["31182574"],"is_preprint":false},{"year":2019,"finding":"IL-17B signals through a heteromeric receptor complex composed of IL-17RA and IL-17RB (not IL-17RB alone) to induce type 2 cytokine secretion from innate type 2 lymphocytes, NKT cells, and CD4+CRTH2+ Th2 cells in humans; IL-17B can augment IL-33-driven type 2 responses.","method":"Primary human lymphocyte cultures, receptor-blocking antibodies, cytokine ELISA, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor subunit-specific blocking antibodies in primary human cells, single lab","pmids":["30770417"],"is_preprint":false},{"year":2025,"finding":"IL-17RB is expressed in the cortex and, together with IL-17RA, mediates the enhancing effect of neuronal IL-17E on social interaction; IL-17E expressed in cortical neurons acts on IL-17RA- and IL-17RB-expressing neurons to enhance social behavior.","method":"Brain-wide receptor expression mapping, genetic manipulation, behavioral assays (social interaction)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — spatial receptor mapping with genetic functional validation in vivo, single paper","pmids":["40199322"],"is_preprint":false},{"year":2017,"finding":"IL17RB/IL17B signaling in breast cancer cells activates NF-κB and upregulates Bcl-2; simultaneous IL17RB siRNA knockdown and doxorubicin treatment induces apoptosis and inhibits migration.","method":"siRNA knockdown, NF-κB and Bcl-2 gene expression assay, Annexin-V apoptosis assay, wound healing migration assay","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 — single lab, KD in one cell line with pathway inference but limited mechanistic depth","pmids":["27372407"],"is_preprint":false},{"year":2017,"finding":"IL17RB promotes liver regeneration by enhancing the growth of small hepatocyte-like progenitor cells (SHPCs); Thy1+ cell-derived extracellular vesicles induce IL17RB expression in SHPCs, and IL17B stimulates the proliferation of small hepatocytes via IL17RB signaling.","method":"GeneChip analysis, cell transplantation model, extracellular vesicle treatment, in vitro growth assay","journal":"Stem cells","confidence":"Low","confidence_rationale":"Tier 3 — correlative expression plus in vitro growth assay, limited direct mechanistic validation of IL17RB signaling","pmids":["27925343"],"is_preprint":false}],"current_model":"IL-17RB functions as a cytokine receptor subunit that forms a heteromeric complex with IL-17RA to transduce signals from IL-17E (IL-25) and IL-17B, activating downstream pathways including NF-κB, ERK1/2, and PI3K to drive type 2 immune responses, Th2 cytokine production, basophil survival and degranulation, and cancer cell proliferation/metastasis; in the brain, IL-17RB additionally mediates neuronal IL-17E signaling to modulate social behavior."},"narrative":{"teleology":[{"year":2000,"claim":"Molecular cloning revealed that IL-17RB (EVI27) encodes a novel IL-17 receptor-family transmembrane protein with multiple isoforms including secreted soluble forms, establishing it as a candidate cytokine receptor expressed on immune cell lineages.","evidence":"Molecular cloning, Northern blot, and Western blot in T-cell, B-cell, and myeloid cell lines","pmids":["10815801"],"confidence":"Medium","gaps":["No ligand identified at this stage","Functional signaling consequence unknown","Single-lab characterization"]},{"year":2001,"claim":"The ligand for IL-17RB was identified as IL-17E (IL-25), and receptor engagement was shown to activate NF-κB and induce IL-8, establishing IL-17RB as a functional signaling receptor.","evidence":"Ligand-receptor binding assay, NF-κB reporter assay, and IL-8 ELISA","pmids":["11058597"],"confidence":"High","gaps":["Co-receptor requirements unknown","Downstream signaling intermediates not mapped","In vivo relevance not tested"]},{"year":2008,"claim":"Genetic and antibody-blocking experiments demonstrated that IL-25 signaling requires a heteromeric IL-17RB/IL-17RA complex, resolving the receptor architecture and explaining why neither subunit alone suffices for biological activity.","evidence":"IL-17RB−/− and IL-17RA−/− mice, antagonistic monoclonal antibodies, splenocyte cytokine assays, and intranasal IL-25 pulmonary inflammation model","pmids":["18768888"],"confidence":"High","gaps":["Stoichiometry and structural basis of the heteromeric complex unresolved","Whether IL-17B also requires IL-17RA was not tested"]},{"year":2009,"claim":"Cell-type-specific expression studies revealed that IL-17RB marks a subset of CD4+ iNKT cells and IL-4-producing myeloid cells, identifying the key innate immune effector populations that drive IL-25-dependent Th2 responses and airway hyperreactivity.","evidence":"Flow cytometry, adoptive transfer into iNKT-deficient mice with AHR readout; cell sorting and 4get reporter mice with anti-SCF neutralization","pmids":["19342692","19828636"],"confidence":"High","gaps":["Molecular basis for selective IL-17RB expression on these subsets unknown","Transcriptional regulation of IL-17RB in iNKT cells not defined"]},{"year":2010,"claim":"IL-17RB was shown to be expressed on basophils and upregulated by IL-3; IL-25 engagement inhibited basophil apoptosis and enhanced IgE-mediated degranulation, extending the receptor's functional scope to granulocyte biology.","evidence":"Flow cytometry, qRT-PCR, Annexin-V apoptosis assay, and β-hexosaminidase degranulation assay on basophils","pmids":["20545698"],"confidence":"Medium","gaps":["Signaling intermediates downstream of IL-17RB in basophils not mapped","Single-lab finding","In vivo basophil-specific role not tested"]},{"year":2012,"claim":"In endothelial cells, IL-25 was found to signal through IL-17RB (but not IL-17RA) via a PI3K-dependent pathway to induce bFGF and angiogenesis, revealing a context where IL-17RB may signal independently of IL-17RA.","evidence":"Receptor-blocking antibodies, siRNA, PI3K inhibitor LY294002, in vitro angiogenesis assay","pmids":["23106660"],"confidence":"Medium","gaps":["Apparent IL-17RA-independence conflicts with KO data; residual IL-17RA expression not excluded","Single lab, in vitro only","PI3K engagement mechanism not defined"]},{"year":2013,"claim":"Prostaglandins PGD2 and PGE2 were shown to suppress Th9 differentiation by downregulating IL-17RB expression via protein kinase A, revealing transcriptional regulation of the receptor as a control point for T-helper subset balance.","evidence":"COX-2 KO mice, synthetic prostaglandins, PKA inhibitors, siRNA, flow cytometry","pmids":["23449692"],"confidence":"Medium","gaps":["Direct PKA target elements in the IL17RB promoter not identified","Whether this applies to other IL-17RB-expressing cell types unknown"]},{"year":2014,"claim":"IL-17RB was implicated in viral oncogenesis: HTLV-1 Tax induces IL-17RB via NF-κB, and IL-17RB is required for Tax-driven NF-κB activation and T-cell immortalization through an IL-9-dependent autocrine loop, placing IL-17RB in a positive feedback circuit in adult T-cell leukemia.","evidence":"RNA-seq, siRNA knockdown, NF-κB reporter, T-cell immortalization assay, ATL patient sample analysis","pmids":["25340344"],"confidence":"High","gaps":["Mechanism by which IL-17RB feeds back to activate NF-κB is unclear","Whether IL-17RB is targetable therapeutically in ATL not tested"]},{"year":2014,"claim":"IL-17RB knockout mice showed reduced Th2-driven immunopathology during RSV infection with a reciprocal increase in Th17 responses, demonstrating that IL-17RB tips the Th2/Th17 balance during respiratory viral infection.","evidence":"IL-17RB−/− mice, RSV infection and asthma exacerbation model, cytokine measurement, AHR assay","pmids":["24407884"],"confidence":"Medium","gaps":["Whether the Th17 shift is a direct consequence of lost IL-17RB signaling or secondary compensation is unresolved","Single lab"]},{"year":2017,"claim":"Multiple studies demonstrated cancer-promoting roles: TGF-β1/Smad signaling upregulates IL-17RB in breast tumors to promote metastasis, and IL-17B/IL-17RB activates ERK1/2-MMP-9 in thyroid cancer to drive invasion, establishing IL-17RB as a signaling hub for tumor progression across cancer types.","evidence":"Syngeneic and xenograft tumor models, Smad and ERK inhibitors, IL-17RB knockdown, invasion/migration assays, clinical samples","pmids":["28993429","28715683"],"confidence":"Medium","gaps":["Whether IL-17RA is required for IL-17B signaling in these cancer contexts was not always addressed","Therapeutic targeting of IL-17RB in tumors not validated"]},{"year":2019,"claim":"Genetic lineage tracing and cell ablation showed IL-17RB marks intestinal tumor stem cells and human colorectal cancer stem cells; ablation of IL-17RB+ cells strongly suppressed tumor growth, establishing IL-17RB as a functional cancer stem cell marker.","evidence":"Il17rb-CreERT2 lineage-tracing mice, CRISPR knockin organoids, xenograft tumor growth with in vivo ablation","pmids":["31182574"],"confidence":"High","gaps":["Whether IL-17RB signaling is required for stemness or is merely a marker is not fully dissected","Upstream signals maintaining IL-17RB in CSCs beyond IL-13 are unknown"]},{"year":2019,"claim":"IL-17B was confirmed to signal through the IL-17RA/IL-17RB heteromeric complex (not IL-17RB alone) in human innate type 2 lymphocytes, NKT cells, and Th2 cells, resolving a longstanding question about whether IL-17B shares the same receptor architecture as IL-25.","evidence":"Receptor-blocking antibodies against IL-17RA and IL-17RB on primary human lymphocytes, cytokine ELISA","pmids":["30770417"],"confidence":"Medium","gaps":["Whether IL-17B and IL-25 compete for binding or engage distinct sites on the complex is unknown","Structural basis for dual ligand recognition not determined"]},{"year":2025,"claim":"IL-17RB was found to be expressed in cortical neurons and, together with IL-17RA, to mediate IL-17E-dependent enhancement of social behavior, extending the receptor's functional role beyond immunity into the central nervous system.","evidence":"Brain-wide receptor expression mapping, genetic manipulation, and social interaction behavioral assays in mice","pmids":["40199322"],"confidence":"Medium","gaps":["Downstream signaling pathway in neurons not characterized","Whether neuronal IL-17RB signals through the same pathways as in immune cells is unknown","Single study"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the IL-17RA/IL-17RB heteromeric complex, how dual ligands (IL-25 and IL-17B) are discriminated, the intracellular signaling adaptors that connect the receptor to NF-κB/ERK/PI3K cascades, and whether IL-17RB signaling in cancer stem cells is a driver of stemness or a bystander marker.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure of IL-17RA/IL-17RB complex","Intracellular adaptor recruitment mechanism undefined","Cancer stem cell role could be correlative"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,3,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,6,8,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4,5,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,11,12]}],"complexes":["IL-17RA/IL-17RB heteromeric receptor complex"],"partners":["IL17RA","IL25","IL17B"],"other_free_text":[]},"mechanistic_narrative":"IL-17RB is a type I transmembrane cytokine receptor that partners with IL-17RA to form the heteromeric signaling complex for IL-17E (IL-25) and IL-17B, transducing signals that drive type 2 immune responses, NF-κB activation, and downstream Th2 cytokine production [PMID:11058597, PMID:18768888, PMID:30770417]. IL-17RB is selectively expressed on innate immune effectors including invariant NKT cells, basophils, and IL-4-producing myeloid cells, where IL-25 engagement promotes Th2 cytokine secretion, inhibits apoptosis, and enhances IgE-mediated degranulation [PMID:19342692, PMID:20545698, PMID:19828636]. Beyond immunity, IL-17RB marks intestinal and colorectal cancer stem cells whose ablation suppresses tumor growth, and IL-17B/IL-17RB signaling in cancer cells activates ERK1/2- and NF-κB-dependent programs promoting invasion, survival, and metastasis [PMID:31182574, PMID:28715683, PMID:28993429]. In the brain, IL-17RB cooperates with IL-17RA on cortical neurons to mediate IL-17E-dependent enhancement of social behavior [PMID:40199322]."},"prefetch_data":{"uniprot":{"accession":"Q9NRM6","full_name":"Interleukin-17 receptor B","aliases":["Cytokine receptor-like 4","IL-17 receptor homolog 1","IL-17Rh1","IL17Rh1","Interleukin-17B receptor","IL-17B receptor"],"length_aa":502,"mass_kda":55.9,"function":"Receptor for the pro-inflammatory cytokines IL17B and IL17E. May play a role in controlling the growth and/or differentiation of hematopoietic cells","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NRM6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17RB","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":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IL17RB","total_profiled":1310},"omim":[{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"},{"mim_id":"605458","title":"INTERLEUKIN 17 RECEPTOR B; IL17RB","url":"https://www.omim.org/entry/605458"},{"mim_id":"604628","title":"INTERLEUKIN 17C; IL17C","url":"https://www.omim.org/entry/604628"},{"mim_id":"604627","title":"INTERLEUKIN 17B; IL17B","url":"https://www.omim.org/entry/604627"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":17.2},{"tissue":"cervix","ntpm":16.9},{"tissue":"kidney","ntpm":55.8},{"tissue":"liver","ntpm":31.1}],"url":"https://www.proteinatlas.org/search/IL17RB"},"hgnc":{"alias_symbol":["IL17RH1","EVI27","CRL4"],"prev_symbol":["IL17BR"]},"alphafold":{"accession":"Q9NRM6","domains":[{"cath_id":"2.60.40.2160","chopping":"23-160","consensus_level":"high","plddt":90.5178,"start":23,"end":160},{"cath_id":"2.60.40.2150","chopping":"178-271","consensus_level":"high","plddt":92.2889,"start":178,"end":271},{"cath_id":"3.40.50.11530","chopping":"333-400_422-487","consensus_level":"high","plddt":81.9181,"start":333,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRM6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRM6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRM6-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17RB","jax_strain_url":"https://www.jax.org/strain/search?query=IL17RB"},"sequence":{"accession":"Q9NRM6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRM6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRM6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRM6"}},"corpus_meta":[{"pmid":"24328678","id":"PMC_24328678","title":"Immunomodulatory 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23892434","citation_count":18,"is_preprint":false},{"pmid":"36715408","id":"PMC_36715408","title":"Recognition of the CCT5 di-Glu degron by CRL4DCAF12 is dependent on TRiC assembly.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/36715408","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49378,"output_tokens":3736,"usd":0.102087},"stage2":{"model":"claude-opus-4-6","input_tokens":7199,"output_tokens":3304,"usd":0.177893},"total_usd":0.27998,"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-17RB (IL-17Rh1/EVI27) was identified as a receptor for the cytokine IL-17E (IL-25), and this interaction induces NF-κB activation and IL-8 production.\",\n      \"method\": \"Ligand-receptor binding assay, NF-κB reporter assay, IL-8 ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original receptor-ligand identification with functional signaling readouts, foundational paper\",\n      \"pmids\": [\"11058597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-17RB (EVI27) encodes a novel transmembrane protein with homology to the IL-17 receptor; multiple isoforms exist including secreted soluble forms produced by intron incorporation or proteolytic cleavage, and it is expressed on selected T-cell, B-cell and myeloid cell lines.\",\n      \"method\": \"Molecular cloning, Northern blot, Western blot, isoform characterization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular and biochemical characterization of protein structure and expression, single lab\",\n      \"pmids\": [\"10815801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-25-mediated biological activities (including IL-5/IL-13 production and pulmonary inflammation) require both IL-17RB and IL-17RA as a heteromeric receptor complex; neither subunit alone is sufficient.\",\n      \"method\": \"Knockout mice (IL-17RB KO and IL-17RA KO), antagonistic monoclonal antibodies, in vitro splenocyte cytokine assay, in vivo intranasal IL-25 model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and antibody blockade with multiple orthogonal in vitro and in vivo readouts, strong mechanistic evidence\",\n      \"pmids\": [\"18768888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RB is highly expressed on a subset of CD4+ invariant NKT (iNKT) cells but not on activated conventional T cells; IL-17RB+ iNKT cells produce large amounts of Th2 cytokines upon IL-25 stimulation and are necessary and sufficient to restore airway hyperreactivity (AHR) in iNKT-deficient mice.\",\n      \"method\": \"Flow cytometry, adoptive transfer into iNKT-deficient mice, intranasal IL-25 AHR model, cytokine assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by FACS, functional reconstitution by adoptive transfer with defined phenotypic readout\",\n      \"pmids\": [\"19342692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RB (IL-25R) is expressed on IL-4-producing CD11b+GR1+ myeloid cells in the lung and bone marrow during chronic allergen challenge; SCF-stimulated c-kit+ eosinophils produce IL-25, and Th2 cytokine production from IL-17RB+ myeloid cells is dependent on SCF.\",\n      \"method\": \"Cell sorting, 4get reporter mice, flow cytometry, anti-SCF neutralization, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct identification of IL-17RB-expressing cell type with functional consequence, single lab\",\n      \"pmids\": [\"19828636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RB is expressed on basophils; IL-3 upregulates IL-17RB mRNA and protein on basophils; IL-25 activation of IL-17RB inhibits basophil apoptosis and enhances IgE-mediated degranulation.\",\n      \"method\": \"Flow cytometry, qRT-PCR, apoptosis assay (Annexin-V), beta-hexosaminidase degranulation assay, ELISA\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional characterization of IL-17RB on basophils with multiple assays, single lab\",\n      \"pmids\": [\"20545698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-25 promotes basic fibroblast growth factor (bFGF) expression and angiogenesis in human endothelial cells through IL-17RB but not IL-17RA, via a PI3K-dependent signaling pathway.\",\n      \"method\": \"Receptor-blocking antibodies, siRNA knockdown, PI3K inhibitor (LY294002), ELISA, in vitro angiogenesis assay, PCR\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific blockade plus signaling pathway inhibitor with functional angiogenesis readout, single lab\",\n      \"pmids\": [\"23106660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COX-2-derived prostaglandins PGD2 and PGE2 suppress Th9 cell differentiation by downregulating IL-17RB expression via a protein kinase A-dependent mechanism.\",\n      \"method\": \"COX-2 KO mice, synthetic prostaglandins, selective inhibitors, siRNA, flow cytometry, real-time PCR, immunoblotting\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and pharmacologic approaches with PKA pathway identified, single lab\",\n      \"pmids\": [\"23449692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17RB is aberrantly overexpressed in HTLV-1 immortalized T cells; Tax induces IL-17RB expression in an IKK/NF-κB-dependent manner; IL-17RB is required for Tax-induced canonical NF-κB activation, HTLV-1-induced immortalization of primary T cells, and survival of HTLV-1 transformed cells via an IL-9-dependent autocrine loop.\",\n      \"method\": \"RNA sequencing, siRNA knockdown, NF-κB reporter assay, T-cell immortalization assay, cytokine measurement, ATL patient sample analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including KD, reporter assay, primary cell transformation, and patient data demonstrating pathway placement\",\n      \"pmids\": [\"25340344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-25 (IL-17E) and IL-17RB promote immunopathology during RSV infection; IL-17RB-/- mice show decreased Th2 and increased Th17 cytokine production along with reduced lung inflammation during RSV infection and RSV-driven asthma exacerbation.\",\n      \"method\": \"IL-17RB knockout mice, RSV infection model, neutralizing antibodies, cytokine measurement, AHR assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined inflammatory phenotype, single lab\",\n      \"pmids\": [\"24407884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGF-β1 secreted by Tregs in tumor-draining lymph nodes upregulates IL-17RB in breast tumor cells via Smad2/3/4 signaling, and IL-17RB upregulation contributes to increased tumor malignancy and distant metastasis.\",\n      \"method\": \"Syngeneic mouse mammary tumor model, TGF-β1 neutralization, Treg depletion, Smad pathway inhibition, xenograft tumor assay, clinical sample analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with multiple interventions and defined downstream signaling pathway, single lab\",\n      \"pmids\": [\"28993429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17B activates IL-17RB in thyroid cancer cells to promote invasion and metastasis via ERK1/2 pathway-mediated MMP-9 upregulation; knockdown of IL-17RB attenuates IL-17B-induced invasion, and ERK1/2 inhibition blocks MMP-9 expression and invasion.\",\n      \"method\": \"IL-17RB knockdown, in vitro invasion/migration assays, in vivo xenograft, Western blot, ERK1/2 inhibitor\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD and pathway inhibitor with both in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"28715683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RB marks intestinal tumor stem cells (TSCs) in mouse intestinal adenomas in an IL-13-dependent manner, and marks cancer stem cells (CSCs) in a subset of human colorectal cancers (hCRCs) that expand independently of IL-13; long-term ablation of IL-17RB-expressing CSCs strongly suppresses tumor growth in vivo.\",\n      \"method\": \"Il17rb-CreERT2 lineage-tracing mice, CRISPR-Cas9 IL17RB-CreERT2 knockin organoids, xenograft tumors, in vivo cell ablation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic lineage tracing in mice and human organoids with xenograft in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"31182574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17B signals through a heteromeric receptor complex composed of IL-17RA and IL-17RB (not IL-17RB alone) to induce type 2 cytokine secretion from innate type 2 lymphocytes, NKT cells, and CD4+CRTH2+ Th2 cells in humans; IL-17B can augment IL-33-driven type 2 responses.\",\n      \"method\": \"Primary human lymphocyte cultures, receptor-blocking antibodies, cytokine ELISA, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor subunit-specific blocking antibodies in primary human cells, single lab\",\n      \"pmids\": [\"30770417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17RB is expressed in the cortex and, together with IL-17RA, mediates the enhancing effect of neuronal IL-17E on social interaction; IL-17E expressed in cortical neurons acts on IL-17RA- and IL-17RB-expressing neurons to enhance social behavior.\",\n      \"method\": \"Brain-wide receptor expression mapping, genetic manipulation, behavioral assays (social interaction)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — spatial receptor mapping with genetic functional validation in vivo, single paper\",\n      \"pmids\": [\"40199322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL17RB/IL17B signaling in breast cancer cells activates NF-κB and upregulates Bcl-2; simultaneous IL17RB siRNA knockdown and doxorubicin treatment induces apoptosis and inhibits migration.\",\n      \"method\": \"siRNA knockdown, NF-κB and Bcl-2 gene expression assay, Annexin-V apoptosis assay, wound healing migration assay\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD in one cell line with pathway inference but limited mechanistic depth\",\n      \"pmids\": [\"27372407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL17RB promotes liver regeneration by enhancing the growth of small hepatocyte-like progenitor cells (SHPCs); Thy1+ cell-derived extracellular vesicles induce IL17RB expression in SHPCs, and IL17B stimulates the proliferation of small hepatocytes via IL17RB signaling.\",\n      \"method\": \"GeneChip analysis, cell transplantation model, extracellular vesicle treatment, in vitro growth assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative expression plus in vitro growth assay, limited direct mechanistic validation of IL17RB signaling\",\n      \"pmids\": [\"27925343\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17RB functions as a cytokine receptor subunit that forms a heteromeric complex with IL-17RA to transduce signals from IL-17E (IL-25) and IL-17B, activating downstream pathways including NF-κB, ERK1/2, and PI3K to drive type 2 immune responses, Th2 cytokine production, basophil survival and degranulation, and cancer cell proliferation/metastasis; in the brain, IL-17RB additionally mediates neuronal IL-17E signaling to modulate social behavior.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-17RB is a type I transmembrane cytokine receptor that partners with IL-17RA to form the heteromeric signaling complex for IL-17E (IL-25) and IL-17B, transducing signals that drive type 2 immune responses, NF-κB activation, and downstream Th2 cytokine production [PMID:11058597, PMID:18768888, PMID:30770417]. IL-17RB is selectively expressed on innate immune effectors including invariant NKT cells, basophils, and IL-4-producing myeloid cells, where IL-25 engagement promotes Th2 cytokine secretion, inhibits apoptosis, and enhances IgE-mediated degranulation [PMID:19342692, PMID:20545698, PMID:19828636]. Beyond immunity, IL-17RB marks intestinal and colorectal cancer stem cells whose ablation suppresses tumor growth, and IL-17B/IL-17RB signaling in cancer cells activates ERK1/2- and NF-κB-dependent programs promoting invasion, survival, and metastasis [PMID:31182574, PMID:28715683, PMID:28993429]. In the brain, IL-17RB cooperates with IL-17RA on cortical neurons to mediate IL-17E-dependent enhancement of social behavior [PMID:40199322].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Molecular cloning revealed that IL-17RB (EVI27) encodes a novel IL-17 receptor-family transmembrane protein with multiple isoforms including secreted soluble forms, establishing it as a candidate cytokine receptor expressed on immune cell lineages.\",\n      \"evidence\": \"Molecular cloning, Northern blot, and Western blot in T-cell, B-cell, and myeloid cell lines\",\n      \"pmids\": [\"10815801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand identified at this stage\", \"Functional signaling consequence unknown\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The ligand for IL-17RB was identified as IL-17E (IL-25), and receptor engagement was shown to activate NF-κB and induce IL-8, establishing IL-17RB as a functional signaling receptor.\",\n      \"evidence\": \"Ligand-receptor binding assay, NF-κB reporter assay, and IL-8 ELISA\",\n      \"pmids\": [\"11058597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-receptor requirements unknown\", \"Downstream signaling intermediates not mapped\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic and antibody-blocking experiments demonstrated that IL-25 signaling requires a heteromeric IL-17RB/IL-17RA complex, resolving the receptor architecture and explaining why neither subunit alone suffices for biological activity.\",\n      \"evidence\": \"IL-17RB−/− and IL-17RA−/− mice, antagonistic monoclonal antibodies, splenocyte cytokine assays, and intranasal IL-25 pulmonary inflammation model\",\n      \"pmids\": [\"18768888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the heteromeric complex unresolved\", \"Whether IL-17B also requires IL-17RA was not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Cell-type-specific expression studies revealed that IL-17RB marks a subset of CD4+ iNKT cells and IL-4-producing myeloid cells, identifying the key innate immune effector populations that drive IL-25-dependent Th2 responses and airway hyperreactivity.\",\n      \"evidence\": \"Flow cytometry, adoptive transfer into iNKT-deficient mice with AHR readout; cell sorting and 4get reporter mice with anti-SCF neutralization\",\n      \"pmids\": [\"19342692\", \"19828636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for selective IL-17RB expression on these subsets unknown\", \"Transcriptional regulation of IL-17RB in iNKT cells not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"IL-17RB was shown to be expressed on basophils and upregulated by IL-3; IL-25 engagement inhibited basophil apoptosis and enhanced IgE-mediated degranulation, extending the receptor's functional scope to granulocyte biology.\",\n      \"evidence\": \"Flow cytometry, qRT-PCR, Annexin-V apoptosis assay, and β-hexosaminidase degranulation assay on basophils\",\n      \"pmids\": [\"20545698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediates downstream of IL-17RB in basophils not mapped\", \"Single-lab finding\", \"In vivo basophil-specific role not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In endothelial cells, IL-25 was found to signal through IL-17RB (but not IL-17RA) via a PI3K-dependent pathway to induce bFGF and angiogenesis, revealing a context where IL-17RB may signal independently of IL-17RA.\",\n      \"evidence\": \"Receptor-blocking antibodies, siRNA, PI3K inhibitor LY294002, in vitro angiogenesis assay\",\n      \"pmids\": [\"23106660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent IL-17RA-independence conflicts with KO data; residual IL-17RA expression not excluded\", \"Single lab, in vitro only\", \"PI3K engagement mechanism not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Prostaglandins PGD2 and PGE2 were shown to suppress Th9 differentiation by downregulating IL-17RB expression via protein kinase A, revealing transcriptional regulation of the receptor as a control point for T-helper subset balance.\",\n      \"evidence\": \"COX-2 KO mice, synthetic prostaglandins, PKA inhibitors, siRNA, flow cytometry\",\n      \"pmids\": [\"23449692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PKA target elements in the IL17RB promoter not identified\", \"Whether this applies to other IL-17RB-expressing cell types unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"IL-17RB was implicated in viral oncogenesis: HTLV-1 Tax induces IL-17RB via NF-κB, and IL-17RB is required for Tax-driven NF-κB activation and T-cell immortalization through an IL-9-dependent autocrine loop, placing IL-17RB in a positive feedback circuit in adult T-cell leukemia.\",\n      \"evidence\": \"RNA-seq, siRNA knockdown, NF-κB reporter, T-cell immortalization assay, ATL patient sample analysis\",\n      \"pmids\": [\"25340344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IL-17RB feeds back to activate NF-κB is unclear\", \"Whether IL-17RB is targetable therapeutically in ATL not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"IL-17RB knockout mice showed reduced Th2-driven immunopathology during RSV infection with a reciprocal increase in Th17 responses, demonstrating that IL-17RB tips the Th2/Th17 balance during respiratory viral infection.\",\n      \"evidence\": \"IL-17RB−/− mice, RSV infection and asthma exacerbation model, cytokine measurement, AHR assay\",\n      \"pmids\": [\"24407884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the Th17 shift is a direct consequence of lost IL-17RB signaling or secondary compensation is unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies demonstrated cancer-promoting roles: TGF-β1/Smad signaling upregulates IL-17RB in breast tumors to promote metastasis, and IL-17B/IL-17RB activates ERK1/2-MMP-9 in thyroid cancer to drive invasion, establishing IL-17RB as a signaling hub for tumor progression across cancer types.\",\n      \"evidence\": \"Syngeneic and xenograft tumor models, Smad and ERK inhibitors, IL-17RB knockdown, invasion/migration assays, clinical samples\",\n      \"pmids\": [\"28993429\", \"28715683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-17RA is required for IL-17B signaling in these cancer contexts was not always addressed\", \"Therapeutic targeting of IL-17RB in tumors not validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic lineage tracing and cell ablation showed IL-17RB marks intestinal tumor stem cells and human colorectal cancer stem cells; ablation of IL-17RB+ cells strongly suppressed tumor growth, establishing IL-17RB as a functional cancer stem cell marker.\",\n      \"evidence\": \"Il17rb-CreERT2 lineage-tracing mice, CRISPR knockin organoids, xenograft tumor growth with in vivo ablation\",\n      \"pmids\": [\"31182574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-17RB signaling is required for stemness or is merely a marker is not fully dissected\", \"Upstream signals maintaining IL-17RB in CSCs beyond IL-13 are unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL-17B was confirmed to signal through the IL-17RA/IL-17RB heteromeric complex (not IL-17RB alone) in human innate type 2 lymphocytes, NKT cells, and Th2 cells, resolving a longstanding question about whether IL-17B shares the same receptor architecture as IL-25.\",\n      \"evidence\": \"Receptor-blocking antibodies against IL-17RA and IL-17RB on primary human lymphocytes, cytokine ELISA\",\n      \"pmids\": [\"30770417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-17B and IL-25 compete for binding or engage distinct sites on the complex is unknown\", \"Structural basis for dual ligand recognition not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IL-17RB was found to be expressed in cortical neurons and, together with IL-17RA, to mediate IL-17E-dependent enhancement of social behavior, extending the receptor's functional role beyond immunity into the central nervous system.\",\n      \"evidence\": \"Brain-wide receptor expression mapping, genetic manipulation, and social interaction behavioral assays in mice\",\n      \"pmids\": [\"40199322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway in neurons not characterized\", \"Whether neuronal IL-17RB signals through the same pathways as in immune cells is unknown\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the IL-17RA/IL-17RB heteromeric complex, how dual ligands (IL-25 and IL-17B) are discriminated, the intracellular signaling adaptors that connect the receptor to NF-κB/ERK/PI3K cascades, and whether IL-17RB signaling in cancer stem cells is a driver of stemness or a bystander marker.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of IL-17RA/IL-17RB complex\", \"Intracellular adaptor recruitment mechanism undefined\", \"Cancer stem cell role could be correlative\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 6, 8, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4, 5, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 11, 12]}\n    ],\n    \"complexes\": [\n      \"IL-17RA/IL-17RB heteromeric receptor complex\"\n    ],\n    \"partners\": [\n      \"IL17RA\",\n      \"IL25\",\n      \"IL17B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}