{"gene":"IL17RC","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2007,"finding":"IL-17RC is the receptor for IL-17F; both IL-17A and IL-17F bind to IL-17RC with high affinity, and a soluble form of IL-17RC effectively blocks binding of both cytokines and inhibits their downstream signaling.","method":"Binding assays, soluble receptor antagonism, signaling inhibition assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — direct ligand-binding assays with functional signaling readout, highly cited foundational paper","pmids":["17911633"],"is_preprint":false},{"year":2010,"finding":"IL-17RC is essential for signaling by IL-17A, IL-17F, and IL-17A/F heterodimers both in vitro and in vivo; IL-17RC does not pre-associate with IL-17RA on the cell surface, but IL-17A induces formation of an IL-17RC/IL-17RA complex; the SEFIR domain of IL-17RC is not required for IL-17A-induced complex formation but is essential for signal transduction; Il-17rc-deficient mice develop milder experimental autoimmune encephalomyelitis.","method":"Il-17rc knockout mice, co-immunoprecipitation, in vitro signaling assays, EAE disease model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular and in vivo phenotypes, co-IP for complex formation, replicated by multiple orthogonal approaches","pmids":["20231694"],"is_preprint":false},{"year":2010,"finding":"IL-17RC inducibly associates with a specific glycosylated isoform of IL-17RA independently of the IL-17RC cytoplasmic tail; the SEFIR domain plus an extended downstream sequence (extended SEFIR) in the IL-17RC cytoplasmic tail are both required for signal transduction; IL-17RC directly interacts with the adaptor/E3 ubiquitin ligase Act1, and functional IL-17RC isoforms containing the extended SEFIR region interact specifically with a phosphorylated isoform of Act1; IL-17RC is required for in vivo IL-17-dependent responses during oral Candida albicans infection.","method":"IL-17RC deletion mutant panel, functional reconstitution in IL-17RC−/− fibroblasts, co-immunoprecipitation with Act1, in vivo oral candidiasis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — structure-function mutagenesis with reconstitution, direct protein interaction assays, in vivo validation","pmids":["20554964"],"is_preprint":false},{"year":2015,"finding":"Autosomal-recessive complete IL-17RC deficiency (homozygous nonsense alleles preventing cell-surface expression) abolishes cellular responses to IL-17A and IL-17F homo- and heterodimers but preserves responses to IL-17E (IL-25), demonstrating that IL-17RC is specifically required for IL-17A/F signaling and is essential for mucocutaneous immunity to Candida albicans.","method":"Patient loss-of-function genetics, cell-surface expression assays (flow cytometry), cellular signaling assays in patient cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — human genetic experiments of nature with direct cellular functional readouts, multiple independent kindreds","pmids":["25918342"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F reveals that IL-17RC forms a symmetrical 2:1 complex with IL-17F homodimer, competing with IL-17RA for cytokine binding; biophysical analysis shows IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC, indicating the possibility of IL-17RA-independent IL-17 signaling through IL-17RC.","method":"X-ray crystallography, biophysical binding assays (SPR/ITC)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biophysical validation, challenges prior receptor complex model","pmids":["32187518"],"is_preprint":false},{"year":2008,"finding":"Both IL-17RA and IL-17RC are required for IL-17A-induced ELR+ CXC chemokine expression and IL-6 secretion in synoviocytes; siRNA knockdown of either receptor nearly completely abrogates IL-17A-induced IL-6, and combined knockdown is needed with TNF-α co-stimulation.","method":"siRNA knockdown of IL-17RA and IL-17RC, ELISA, microarray","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — dual receptor siRNA with cytokine readout, single lab","pmids":["18097068"],"is_preprint":false},{"year":2020,"finding":"IL-17RC signaling in adipocytes drives expression of TGFβ1, which promotes local sympathetic innervation of thermogenic adipose tissue; adipose-specific ablation of IL-17RC reduces TGFβ1 expression, impairs sympathetic innervation, and causes obesity and metabolic phenotypes consistent with defective thermogenesis; innervation is fully rescued by restoring TGFβ1 expression; γδ T cells signal through IL-17RC on adipocytes to mediate this effect.","method":"Adipose-specific IL-17RC knockout mice, TGFβ1 rescue experiments, sympathetic innervation imaging, metabolic phenotyping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific genetic KO with rescue experiment and defined downstream mechanism (TGFβ1), replicated across tissue types","pmids":["32076265"],"is_preprint":false},{"year":2007,"finding":"IL-17RC produces multiple protein isoforms detectable by antibodies against the intracellular domain (ICD) or extracellular domain (ECD); the full-length IL-17RC isoform inhibits apoptosis in prostate cancer cells; different isoforms are differentially expressed in androgen-dependent versus androgen-independent prostate cancer.","method":"Western blotting with domain-specific antibodies, immunohistochemistry of tissue microarrays","journal":"Neoplasia","confidence":"Low","confidence_rationale":"Tier 3 — protein isoform detection by antibody, functional anti-apoptotic role inferred from isoform identity, single lab","pmids":["17603628"],"is_preprint":false},{"year":2017,"finding":"Follistatin-like protein 1 (FSTL-1) is required for IL17rc gene transcription and IL-17RC surface protein expression in bone marrow stromal cells; loss of FSTL-1 reduces IL-17RC expression and impairs IL-17-dependent cytokine production (IL-6 and G-CSF).","method":"In vitro FSTL-1 suppression in bone marrow stromal cells, microarray, surface protein expression assays","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — gene expression and surface protein readout with functional cytokine assay, single lab","pmids":["28377613"],"is_preprint":false},{"year":2017,"finding":"IL-17RC knockdown in B16 melanoma and 4T1 carcinoma cells causes aberrant expression and activation of JNK isoforms and markedly diminished levels of the ubiquitin-editing enzyme A20; differential upregulation of JNK1 versus JNK2 accounts for reciprocal regulation of c-Jun activity and tumor-specific proliferation; reconstitution with full-length A20 (but not a truncation mutant) reverses aberrant JNK activities, placing IL-17RC upstream of A20 in controlling JNK isoform-dependent tumor cell proliferation.","method":"siRNA knockdown, A20 reconstitution with full-length vs truncation mutant, western blotting, in vitro and in vivo tumor proliferation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis defined by rescue with specific A20 constructs, two cell line models, single lab","pmids":["28562353"],"is_preprint":false},{"year":2017,"finding":"UVB irradiation reduces IL-17RA and IL-17RC expression on human dermal fibroblasts via a TGF-β1/Smad3 signaling pathway, thereby inhibiting IL-17A/TNF-α-induced IL-6, IL-8, and CXCL-1 production.","method":"UVB irradiation of cultured fibroblasts, qPCR, western blot, ELISA, flow cytometry","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 — receptor downregulation mechanism inferred from correlation with TGF-β1/Smad3 pathway, single lab","pmids":["28217129"],"is_preprint":false},{"year":2019,"finding":"An IL-17RC rs199772854A missense mutation increases IL-17RC gene expression in osteoblasts, upregulates TRAF6 and NF-κB in the IL-17 signaling axis, and significantly increases expression of osteogenic markers, promoting osteoblast differentiation.","method":"Mutagenesis in mouse embryonic osteoblast (3T3-E1) model, RT-qPCR, western blot","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — cell line overexpression with pathway readout, single lab, no direct mechanistic reconstitution","pmids":["30864693"],"is_preprint":false},{"year":2023,"finding":"A homozygous duplication variant in IL17RC (involving exon 13, creating a premature stop codon) is loss-of-function; patient SV40-immortalized fibroblasts lack response to IL-17A, and this is rescued by introducing wild-type IL17RC, establishing the variant as the cause of AR IL-17RC deficiency and CMC.","method":"IL17RC-knockout cell line complementation, flow cytometry, qPCR, immunoblotting, RNA-sequencing","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue experiment with WT IL17RC in patient-derived cells, multiple orthogonal methods","pmids":["38129603"],"is_preprint":false}],"current_model":"IL-17RC is a transmembrane receptor subunit that binds IL-17A and IL-17F (forming a symmetrical 2:1 complex with IL-17F homodimer as revealed by crystal structure), is recruited by IL-17A to form a signaling complex with IL-17RA, and transduces signals via its cytoplasmic SEFIR domain plus an extended downstream sequence that directly engages the adaptor/E3 ubiquitin ligase Act1; in adipocytes, IL-17RC drives TGFβ1 expression downstream of γδ T cell IL-17 signals to promote sympathetic innervation, and complete loss of IL-17RC abolishes responses to IL-17A and IL-17F but not IL-17E, establishing its essential and selective role in mucocutaneous antifungal immunity."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing IL-17RC as a high-affinity receptor for both IL-17A and IL-17F resolved which receptor subunit directly engages these cytokines and showed that soluble IL-17RC can block both ligands, defining IL-17RC as a potential therapeutic target.","evidence":"Direct ligand-binding assays and soluble receptor antagonism with signaling inhibition readouts","pmids":["17911633"],"confidence":"High","gaps":["Stoichiometry of the receptor complex was unknown","Whether IL-17RC signals independently of IL-17RA was not addressed","Intracellular signaling domains required for transduction were not mapped"]},{"year":2008,"claim":"Demonstrating that both IL-17RA and IL-17RC are required for IL-17A-induced chemokine and IL-6 production in synoviocytes established that neither receptor alone is sufficient, implying obligate hetero-receptor signaling.","evidence":"siRNA knockdown of IL-17RA and IL-17RC individually and in combination in human synoviocytes with ELISA readout","pmids":["18097068"],"confidence":"Medium","gaps":["Mechanism of receptor cooperation was not defined","Physical association of the two receptors was not tested"]},{"year":2010,"claim":"Genetic deletion and structure-function analysis revealed that IL-17RC does not pre-associate with IL-17RA but is recruited upon IL-17A binding; the SEFIR domain plus an extended downstream cytoplasmic sequence directly engages the phosphorylated form of the adaptor Act1, establishing the core intracellular signaling mechanism.","evidence":"Il-17rc knockout mice, IL-17RC deletion mutant reconstitution in IL-17RC−/− fibroblasts, co-immunoprecipitation with Act1, oral candidiasis model, EAE disease model","pmids":["20231694","20554964"],"confidence":"High","gaps":["Structural basis of the IL-17RC–Act1 SEFIR–SEFIR interaction was not resolved","How glycosylation of IL-17RA isoforms affects complex assembly remained unclear","Whether IL-17RC has signaling capacity independent of IL-17RA was not tested"]},{"year":2015,"claim":"Human autosomal-recessive IL-17RC deficiency proved that IL-17RC is specifically required for IL-17A and IL-17F signaling (but not IL-17E) and is essential for mucocutaneous antifungal immunity, linking the receptor to chronic mucocutaneous candidiasis.","evidence":"Homozygous loss-of-function patient genetics with flow cytometry and cellular signaling assays in patient-derived cells across multiple kindreds","pmids":["25918342"],"confidence":"High","gaps":["Residual IL-17 signaling via alternative receptors was not excluded in all tissues","Whether partial IL-17RC deficiency produces an intermediate phenotype was not determined"]},{"year":2017,"claim":"IL-17RC was placed upstream of the ubiquitin-editing enzyme A20 and JNK isoform-specific signaling in tumor cells, showing that loss of IL-17RC causes aberrant JNK activation correctable by A20 reconstitution, and separately, FSTL-1 was identified as a transcriptional regulator of IL-17RC expression in bone marrow stromal cells.","evidence":"siRNA knockdown and A20 reconstitution in melanoma/carcinoma lines; FSTL-1 suppression with surface protein expression and cytokine assays in stromal cells","pmids":["28562353","28377613"],"confidence":"Medium","gaps":["Direct physical interaction between IL-17RC signaling and A20 regulation was not shown","FSTL-1 transcriptional control of IL17RC was demonstrated in one cell type only","Relevance of IL-17RC–A20–JNK axis in non-tumor physiology not tested"]},{"year":2020,"claim":"The crystal structure of IL-17RC extracellular domain bound to IL-17F revealed a symmetrical 2:1 stoichiometry where two IL-17RC molecules occupy both binding sites on the cytokine homodimer, competing with IL-17RA and raising the possibility of IL-17RA-independent signaling.","evidence":"X-ray crystallography of IL-17RC ECD–IL-17F complex, SPR/ITC biophysical binding assays","pmids":["32187518"],"confidence":"High","gaps":["Functional signaling through a 2:1 IL-17RC homodimeric receptor complex was not demonstrated in cells","Structural basis of the ternary IL-17RA/IL-17RC/cytokine complex remains unresolved"]},{"year":2020,"claim":"A non-immune role for IL-17RC was established in adipocytes, where γδ T cell-derived IL-17 signals through IL-17RC to induce TGFβ1, which in turn promotes sympathetic innervation of thermogenic fat; adipose-specific IL-17RC ablation causes obesity rescued by TGFβ1 restoration.","evidence":"Adipose-specific IL-17RC conditional knockout mice with TGFβ1 rescue, sympathetic innervation imaging, metabolic phenotyping","pmids":["32076265"],"confidence":"High","gaps":["Whether this pathway operates through the canonical Act1-dependent mechanism was not tested","Contribution of IL-17A vs IL-17F to adipocyte signaling was not distinguished"]},{"year":2023,"claim":"Functional rescue of a novel homozygous IL17RC duplication variant in patient fibroblasts confirmed that AR IL-17RC loss-of-function is the genetic cause of chronic mucocutaneous candidiasis, reinforcing the human genetic evidence.","evidence":"Wild-type IL17RC complementation of SV40-immortalized patient fibroblasts with flow cytometry, qPCR, immunoblotting, and RNA-seq","pmids":["38129603"],"confidence":"Medium","gaps":["Genotype–phenotype correlation across partial vs complete IL-17RC deficiency is still limited to few families","Broader immune phenotyping beyond CMC not performed"]},{"year":null,"claim":"Key unresolved questions include whether IL-17RC homodimeric (2:1) complexes signal independently of IL-17RA in physiological contexts, the structural basis of the intracellular SEFIR–Act1 interaction, and the full spectrum of tissue-specific IL-17RC functions beyond immunity and adipose thermogenesis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for the IL-17RC intracellular domain or its complex with Act1","Functional significance of multiple IL-17RC splice isoforms in vivo is unknown","Whether IL-17RC participates in signaling by other IL-17 family members beyond IL-17A/F remains untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,4]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["IL17RA","ACT1","IL17A","IL17F"],"other_free_text":[]},"mechanistic_narrative":"IL-17RC is a transmembrane cytokine receptor subunit essential for cellular responses to IL-17A, IL-17F, and IL-17A/F heterodimers, but dispensable for IL-17E (IL-25) signaling [PMID:17911633, PMID:25918342]. Upon ligand engagement, IL-17A induces recruitment of IL-17RC to IL-17RA to form a signaling-competent heteromeric complex; the cytoplasmic SEFIR domain and an extended downstream sequence of IL-17RC directly engage the adaptor/E3 ubiquitin ligase Act1 to initiate downstream signaling, while a 2:1 IL-17RC:IL-17F stoichiometry revealed by crystal structure demonstrates that IL-17RC can also occupy both binding sites on the cytokine homodimer independently of IL-17RA [PMID:20231694, PMID:20554964, PMID:32187518]. Beyond canonical immune signaling—where IL-17RC is required for mucocutaneous antifungal defense against Candida albicans—IL-17RC in adipocytes transduces γδ T cell-derived IL-17 signals to drive TGFβ1 expression, thereby promoting sympathetic innervation of thermogenic adipose tissue [PMID:20554964, PMID:32076265]. Autosomal-recessive IL-17RC deficiency causes chronic mucocutaneous candidiasis in humans [PMID:25918342, PMID:38129603]."},"prefetch_data":{"uniprot":{"accession":"Q8NAC3","full_name":"Interleukin-17 receptor C","aliases":["Interleukin-17 receptor homolog","IL17Rhom","Interleukin-17 receptor-like protein","IL-17RL","ZcytoR14"],"length_aa":791,"mass_kda":86.2,"function":"Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (By similarity). Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RA (PubMed:16785495). Receptor for the heterodimer formed by IL17A and IL17B as part of a heterodimeric complex with IL17RA (PubMed:18684971). Has also been shown to be the cognate receptor for IL17F and to bind IL17A with high affinity without the need for IL17RA (PubMed:17911633). Upon binding of IL17F homodimer triggers downstream activation of TRAF6 and NF-kappa-B signaling pathway (PubMed:16785495, PubMed:32187518). Induces transcriptional activation of IL33, a potent cytokine that stimulates group 2 innate lymphoid cells and adaptive T-helper 2 cells involved in pulmonary allergic response to fungi (By similarity). Promotes sympathetic innervation of peripheral organs by coordinating the communication between gamma-delta T cells and parenchymal cells. Stimulates sympathetic innervation of thermogenic adipose tissue by driving TGFB1 expression (By similarity). Binding of IL17A-IL17F to IL17RA-IL17RC heterodimeric receptor complex triggers homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter through SEFIR domains. This leads to downstream TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:17911633, PubMed:18684971). Primarily induces neutrophil activation and recruitment at infection and inflammatory sites (By similarity). Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity) Receptor for both IL17A and IL17F Does not bind IL17A or IL17F Does not bind IL17A or IL17F Receptor for both IL17A and IL17F","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NAC3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17RC","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL17RC","total_profiled":1310},"omim":[{"mim_id":"616445","title":"CANDIDIASIS, FAMILIAL, 9; CANDF9","url":"https://www.omim.org/entry/616445"},{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"613956","title":"CANDIDIASIS, FAMILIAL, 6; CANDF6","url":"https://www.omim.org/entry/613956"},{"mim_id":"610925","title":"INTERLEUKIN 17 RECEPTOR C; IL17RC","url":"https://www.omim.org/entry/610925"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL17RC"},"hgnc":{"alias_symbol":["IL17-RL"],"prev_symbol":[]},"alphafold":{"accession":"Q8NAC3","domains":[{"cath_id":"2.60.40.2160","chopping":"91-96_104-167_191-273","consensus_level":"high","plddt":81.4676,"start":91,"end":273},{"cath_id":"2.60.40,2.60.40","chopping":"281-367","consensus_level":"medium","plddt":82.7294,"start":281,"end":367},{"cath_id":"-","chopping":"465-558","consensus_level":"medium","plddt":86.8651,"start":465,"end":558},{"cath_id":"3.40.50.11530","chopping":"586-666_678-768","consensus_level":"high","plddt":82.628,"start":586,"end":768}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NAC3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NAC3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NAC3-F1-predicted_aligned_error_v6.png","plddt_mean":73.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17RC","jax_strain_url":"https://www.jax.org/strain/search?query=IL17RC"},"sequence":{"accession":"Q8NAC3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NAC3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NAC3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NAC3"}},"corpus_meta":[{"pmid":"17911633","id":"PMC_17911633","title":"Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17911633","citation_count":281,"is_preprint":false},{"pmid":"25918342","id":"PMC_25918342","title":"Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis.","date":"2015","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25918342","citation_count":149,"is_preprint":false},{"pmid":"32076265","id":"PMC_32076265","title":"γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32076265","citation_count":147,"is_preprint":false},{"pmid":"23177625","id":"PMC_23177625","title":"Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.","date":"2012","source":"Cell 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Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/36125689","citation_count":26,"is_preprint":false},{"pmid":"27155366","id":"PMC_27155366","title":"Neutrophils from F508del cystic fibrosis patients produce IL-17A and express IL-23 - dependent IL-17RC.","date":"2016","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/27155366","citation_count":25,"is_preprint":false},{"pmid":"22999050","id":"PMC_22999050","title":"A single-nucleotide polymorphism rs708567 in the IL-17RC gene is associated with a susceptibility to and the curve severity of adolescent idiopathic scoliosis in a Chinese Han population: a case-control study.","date":"2012","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/22999050","citation_count":24,"is_preprint":false},{"pmid":"28298222","id":"PMC_28298222","title":"Increased IL-17RA and IL-17RC in End-Stage COPD and the Contribution to Mast Cell Secretion of FGF-2 and VEGF.","date":"2017","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/28298222","citation_count":21,"is_preprint":false},{"pmid":"31572359","id":"PMC_31572359","title":"Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31572359","citation_count":19,"is_preprint":false},{"pmid":"28217129","id":"PMC_28217129","title":"Ultraviolet B Inhibits IL-17A/TNF-α-Stimulated Activation of Human Dermal Fibroblasts by Decreasing the Expression of IL-17RA and IL-17RC on Fibroblasts.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28217129","citation_count":18,"is_preprint":false},{"pmid":"26731132","id":"PMC_26731132","title":"Probable Chemical Hypoxia Effects on Progress of CNV Through Induction of Promoter CpG Demethylation and Overexpression of IL17RC in Human RPE Cells.","date":"2016","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/26731132","citation_count":17,"is_preprint":false},{"pmid":"29764467","id":"PMC_29764467","title":"Association of IL17RC and COL6A1 genetic polymorphisms with susceptibility to ossification of the thoracic posterior longitudinal ligament in Chinese patients.","date":"2018","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/29764467","citation_count":15,"is_preprint":false},{"pmid":"34180764","id":"PMC_34180764","title":"Self-assembled chitosan nanoparticles for intranasal delivery of recombinant protein interleukin-17 receptor C (IL-17RC): preparation and evaluation in asthma mice.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34180764","citation_count":13,"is_preprint":false},{"pmid":"28377613","id":"PMC_28377613","title":"Follistatin-like protein 1 modulates IL-17 signaling via IL-17RC regulation in stromal cells.","date":"2017","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28377613","citation_count":12,"is_preprint":false},{"pmid":"24885153","id":"PMC_24885153","title":"Overexpression of IL-17RC associated with ocular sarcoidosis.","date":"2014","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24885153","citation_count":12,"is_preprint":false},{"pmid":"30864693","id":"PMC_30864693","title":"Potential role of the IL17RC gene in the thoracic ossification of the posterior longitudinal ligament.","date":"2019","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30864693","citation_count":10,"is_preprint":false},{"pmid":"34171369","id":"PMC_34171369","title":"Identification of two interleukin 17 receptor C (IL-17RC) genes and their binding activities to three IL-17A/F ligands in the Japanese medaka, Oryzias latipes.","date":"2021","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34171369","citation_count":10,"is_preprint":false},{"pmid":"22744455","id":"PMC_22744455","title":"Association study of IL-17RC, CHL1, DSCAM and CNTNAP2 genes polymorphisms with adolescent idiopathic scoliosis susceptibility in a Chinese Han population.","date":"2012","source":"Studies in health technology and informatics","url":"https://pubmed.ncbi.nlm.nih.gov/22744455","citation_count":9,"is_preprint":false},{"pmid":"28562353","id":"PMC_28562353","title":"IL-17RC is critically required to maintain baseline A20 production to repress JNK isoform-dependent tumor-specific proliferation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28562353","citation_count":8,"is_preprint":false},{"pmid":"31291973","id":"PMC_31291973","title":"IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament.","date":"2019","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/31291973","citation_count":6,"is_preprint":false},{"pmid":"38129603","id":"PMC_38129603","title":"Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC.","date":"2023","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38129603","citation_count":4,"is_preprint":false},{"pmid":"40239933","id":"PMC_40239933","title":"Evolutionary insights and poly(I:C)-induced changes in expression and m6A modifications of il17ra and il17rc in Miichthysmiiuy.","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40239933","citation_count":2,"is_preprint":false},{"pmid":"40887867","id":"PMC_40887867","title":"The Association of IL-17RC Polymorphisms rs708567 and rs76999397 With Acute Lymphoblastic Leukaemia.","date":"2025","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/40887867","citation_count":1,"is_preprint":false},{"pmid":"37577484","id":"PMC_37577484","title":"Isolated chronic mucocutaneous candidiasis due to a novel duplication variant of IL17RC.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37577484","citation_count":1,"is_preprint":false},{"pmid":"41959117","id":"PMC_41959117","title":"IL-17RC signaling connects intestinal microbiota and neuroimmune interactions in atherosclerosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41959117","citation_count":0,"is_preprint":false},{"pmid":"40813448","id":"PMC_40813448","title":"Identification of an IL17RC missense variant in a Chinese family with multiple osteochondromas and ankylosing spondylitis.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40813448","citation_count":0,"is_preprint":false},{"pmid":"37254819","id":"PMC_37254819","title":"Oral candidiasis and seborrheic dermatitis in an 8-year-old female with a heterozygous variant of the IL-17RC gene.","date":"2023","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/37254819","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19816,"output_tokens":3242,"usd":0.054039},"stage2":{"model":"claude-opus-4-6","input_tokens":6661,"output_tokens":4932,"usd":0.234907},"total_usd":0.288946,"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\": 2007,\n      \"finding\": \"IL-17RC is the receptor for IL-17F; both IL-17A and IL-17F bind to IL-17RC with high affinity, and a soluble form of IL-17RC effectively blocks binding of both cytokines and inhibits their downstream signaling.\",\n      \"method\": \"Binding assays, soluble receptor antagonism, signaling inhibition assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct ligand-binding assays with functional signaling readout, highly cited foundational paper\",\n      \"pmids\": [\"17911633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RC is essential for signaling by IL-17A, IL-17F, and IL-17A/F heterodimers both in vitro and in vivo; IL-17RC does not pre-associate with IL-17RA on the cell surface, but IL-17A induces formation of an IL-17RC/IL-17RA complex; the SEFIR domain of IL-17RC is not required for IL-17A-induced complex formation but is essential for signal transduction; Il-17rc-deficient mice develop milder experimental autoimmune encephalomyelitis.\",\n      \"method\": \"Il-17rc knockout mice, co-immunoprecipitation, in vitro signaling assays, EAE disease model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular and in vivo phenotypes, co-IP for complex formation, replicated by multiple orthogonal approaches\",\n      \"pmids\": [\"20231694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RC inducibly associates with a specific glycosylated isoform of IL-17RA independently of the IL-17RC cytoplasmic tail; the SEFIR domain plus an extended downstream sequence (extended SEFIR) in the IL-17RC cytoplasmic tail are both required for signal transduction; IL-17RC directly interacts with the adaptor/E3 ubiquitin ligase Act1, and functional IL-17RC isoforms containing the extended SEFIR region interact specifically with a phosphorylated isoform of Act1; IL-17RC is required for in vivo IL-17-dependent responses during oral Candida albicans infection.\",\n      \"method\": \"IL-17RC deletion mutant panel, functional reconstitution in IL-17RC−/− fibroblasts, co-immunoprecipitation with Act1, in vivo oral candidiasis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structure-function mutagenesis with reconstitution, direct protein interaction assays, in vivo validation\",\n      \"pmids\": [\"20554964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Autosomal-recessive complete IL-17RC deficiency (homozygous nonsense alleles preventing cell-surface expression) abolishes cellular responses to IL-17A and IL-17F homo- and heterodimers but preserves responses to IL-17E (IL-25), demonstrating that IL-17RC is specifically required for IL-17A/F signaling and is essential for mucocutaneous immunity to Candida albicans.\",\n      \"method\": \"Patient loss-of-function genetics, cell-surface expression assays (flow cytometry), cellular signaling assays in patient cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic experiments of nature with direct cellular functional readouts, multiple independent kindreds\",\n      \"pmids\": [\"25918342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F reveals that IL-17RC forms a symmetrical 2:1 complex with IL-17F homodimer, competing with IL-17RA for cytokine binding; biophysical analysis shows IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC, indicating the possibility of IL-17RA-independent IL-17 signaling through IL-17RC.\",\n      \"method\": \"X-ray crystallography, biophysical binding assays (SPR/ITC)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biophysical validation, challenges prior receptor complex model\",\n      \"pmids\": [\"32187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Both IL-17RA and IL-17RC are required for IL-17A-induced ELR+ CXC chemokine expression and IL-6 secretion in synoviocytes; siRNA knockdown of either receptor nearly completely abrogates IL-17A-induced IL-6, and combined knockdown is needed with TNF-α co-stimulation.\",\n      \"method\": \"siRNA knockdown of IL-17RA and IL-17RC, ELISA, microarray\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual receptor siRNA with cytokine readout, single lab\",\n      \"pmids\": [\"18097068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17RC signaling in adipocytes drives expression of TGFβ1, which promotes local sympathetic innervation of thermogenic adipose tissue; adipose-specific ablation of IL-17RC reduces TGFβ1 expression, impairs sympathetic innervation, and causes obesity and metabolic phenotypes consistent with defective thermogenesis; innervation is fully rescued by restoring TGFβ1 expression; γδ T cells signal through IL-17RC on adipocytes to mediate this effect.\",\n      \"method\": \"Adipose-specific IL-17RC knockout mice, TGFβ1 rescue experiments, sympathetic innervation imaging, metabolic phenotyping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific genetic KO with rescue experiment and defined downstream mechanism (TGFβ1), replicated across tissue types\",\n      \"pmids\": [\"32076265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-17RC produces multiple protein isoforms detectable by antibodies against the intracellular domain (ICD) or extracellular domain (ECD); the full-length IL-17RC isoform inhibits apoptosis in prostate cancer cells; different isoforms are differentially expressed in androgen-dependent versus androgen-independent prostate cancer.\",\n      \"method\": \"Western blotting with domain-specific antibodies, immunohistochemistry of tissue microarrays\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — protein isoform detection by antibody, functional anti-apoptotic role inferred from isoform identity, single lab\",\n      \"pmids\": [\"17603628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Follistatin-like protein 1 (FSTL-1) is required for IL17rc gene transcription and IL-17RC surface protein expression in bone marrow stromal cells; loss of FSTL-1 reduces IL-17RC expression and impairs IL-17-dependent cytokine production (IL-6 and G-CSF).\",\n      \"method\": \"In vitro FSTL-1 suppression in bone marrow stromal cells, microarray, surface protein expression assays\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gene expression and surface protein readout with functional cytokine assay, single lab\",\n      \"pmids\": [\"28377613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17RC knockdown in B16 melanoma and 4T1 carcinoma cells causes aberrant expression and activation of JNK isoforms and markedly diminished levels of the ubiquitin-editing enzyme A20; differential upregulation of JNK1 versus JNK2 accounts for reciprocal regulation of c-Jun activity and tumor-specific proliferation; reconstitution with full-length A20 (but not a truncation mutant) reverses aberrant JNK activities, placing IL-17RC upstream of A20 in controlling JNK isoform-dependent tumor cell proliferation.\",\n      \"method\": \"siRNA knockdown, A20 reconstitution with full-length vs truncation mutant, western blotting, in vitro and in vivo tumor proliferation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis defined by rescue with specific A20 constructs, two cell line models, single lab\",\n      \"pmids\": [\"28562353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UVB irradiation reduces IL-17RA and IL-17RC expression on human dermal fibroblasts via a TGF-β1/Smad3 signaling pathway, thereby inhibiting IL-17A/TNF-α-induced IL-6, IL-8, and CXCL-1 production.\",\n      \"method\": \"UVB irradiation of cultured fibroblasts, qPCR, western blot, ELISA, flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — receptor downregulation mechanism inferred from correlation with TGF-β1/Smad3 pathway, single lab\",\n      \"pmids\": [\"28217129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An IL-17RC rs199772854A missense mutation increases IL-17RC gene expression in osteoblasts, upregulates TRAF6 and NF-κB in the IL-17 signaling axis, and significantly increases expression of osteogenic markers, promoting osteoblast differentiation.\",\n      \"method\": \"Mutagenesis in mouse embryonic osteoblast (3T3-E1) model, RT-qPCR, western blot\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — cell line overexpression with pathway readout, single lab, no direct mechanistic reconstitution\",\n      \"pmids\": [\"30864693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A homozygous duplication variant in IL17RC (involving exon 13, creating a premature stop codon) is loss-of-function; patient SV40-immortalized fibroblasts lack response to IL-17A, and this is rescued by introducing wild-type IL17RC, establishing the variant as the cause of AR IL-17RC deficiency and CMC.\",\n      \"method\": \"IL17RC-knockout cell line complementation, flow cytometry, qPCR, immunoblotting, RNA-sequencing\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiment with WT IL17RC in patient-derived cells, multiple orthogonal methods\",\n      \"pmids\": [\"38129603\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17RC is a transmembrane receptor subunit that binds IL-17A and IL-17F (forming a symmetrical 2:1 complex with IL-17F homodimer as revealed by crystal structure), is recruited by IL-17A to form a signaling complex with IL-17RA, and transduces signals via its cytoplasmic SEFIR domain plus an extended downstream sequence that directly engages the adaptor/E3 ubiquitin ligase Act1; in adipocytes, IL-17RC drives TGFβ1 expression downstream of γδ T cell IL-17 signals to promote sympathetic innervation, and complete loss of IL-17RC abolishes responses to IL-17A and IL-17F but not IL-17E, establishing its essential and selective role in mucocutaneous antifungal immunity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-17RC is a transmembrane cytokine receptor subunit essential for cellular responses to IL-17A, IL-17F, and IL-17A/F heterodimers, but dispensable for IL-17E (IL-25) signaling [PMID:17911633, PMID:25918342]. Upon ligand engagement, IL-17A induces recruitment of IL-17RC to IL-17RA to form a signaling-competent heteromeric complex; the cytoplasmic SEFIR domain and an extended downstream sequence of IL-17RC directly engage the adaptor/E3 ubiquitin ligase Act1 to initiate downstream signaling, while a 2:1 IL-17RC:IL-17F stoichiometry revealed by crystal structure demonstrates that IL-17RC can also occupy both binding sites on the cytokine homodimer independently of IL-17RA [PMID:20231694, PMID:20554964, PMID:32187518]. Beyond canonical immune signaling—where IL-17RC is required for mucocutaneous antifungal defense against Candida albicans—IL-17RC in adipocytes transduces γδ T cell-derived IL-17 signals to drive TGFβ1 expression, thereby promoting sympathetic innervation of thermogenic adipose tissue [PMID:20554964, PMID:32076265]. Autosomal-recessive IL-17RC deficiency causes chronic mucocutaneous candidiasis in humans [PMID:25918342, PMID:38129603].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing IL-17RC as a high-affinity receptor for both IL-17A and IL-17F resolved which receptor subunit directly engages these cytokines and showed that soluble IL-17RC can block both ligands, defining IL-17RC as a potential therapeutic target.\",\n      \"evidence\": \"Direct ligand-binding assays and soluble receptor antagonism with signaling inhibition readouts\",\n      \"pmids\": [\"17911633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the receptor complex was unknown\", \"Whether IL-17RC signals independently of IL-17RA was not addressed\", \"Intracellular signaling domains required for transduction were not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that both IL-17RA and IL-17RC are required for IL-17A-induced chemokine and IL-6 production in synoviocytes established that neither receptor alone is sufficient, implying obligate hetero-receptor signaling.\",\n      \"evidence\": \"siRNA knockdown of IL-17RA and IL-17RC individually and in combination in human synoviocytes with ELISA readout\",\n      \"pmids\": [\"18097068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of receptor cooperation was not defined\", \"Physical association of the two receptors was not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic deletion and structure-function analysis revealed that IL-17RC does not pre-associate with IL-17RA but is recruited upon IL-17A binding; the SEFIR domain plus an extended downstream cytoplasmic sequence directly engages the phosphorylated form of the adaptor Act1, establishing the core intracellular signaling mechanism.\",\n      \"evidence\": \"Il-17rc knockout mice, IL-17RC deletion mutant reconstitution in IL-17RC−/− fibroblasts, co-immunoprecipitation with Act1, oral candidiasis model, EAE disease model\",\n      \"pmids\": [\"20231694\", \"20554964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the IL-17RC–Act1 SEFIR–SEFIR interaction was not resolved\", \"How glycosylation of IL-17RA isoforms affects complex assembly remained unclear\", \"Whether IL-17RC has signaling capacity independent of IL-17RA was not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Human autosomal-recessive IL-17RC deficiency proved that IL-17RC is specifically required for IL-17A and IL-17F signaling (but not IL-17E) and is essential for mucocutaneous antifungal immunity, linking the receptor to chronic mucocutaneous candidiasis.\",\n      \"evidence\": \"Homozygous loss-of-function patient genetics with flow cytometry and cellular signaling assays in patient-derived cells across multiple kindreds\",\n      \"pmids\": [\"25918342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual IL-17 signaling via alternative receptors was not excluded in all tissues\", \"Whether partial IL-17RC deficiency produces an intermediate phenotype was not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"IL-17RC was placed upstream of the ubiquitin-editing enzyme A20 and JNK isoform-specific signaling in tumor cells, showing that loss of IL-17RC causes aberrant JNK activation correctable by A20 reconstitution, and separately, FSTL-1 was identified as a transcriptional regulator of IL-17RC expression in bone marrow stromal cells.\",\n      \"evidence\": \"siRNA knockdown and A20 reconstitution in melanoma/carcinoma lines; FSTL-1 suppression with surface protein expression and cytokine assays in stromal cells\",\n      \"pmids\": [\"28562353\", \"28377613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between IL-17RC signaling and A20 regulation was not shown\", \"FSTL-1 transcriptional control of IL17RC was demonstrated in one cell type only\", \"Relevance of IL-17RC–A20–JNK axis in non-tumor physiology not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The crystal structure of IL-17RC extracellular domain bound to IL-17F revealed a symmetrical 2:1 stoichiometry where two IL-17RC molecules occupy both binding sites on the cytokine homodimer, competing with IL-17RA and raising the possibility of IL-17RA-independent signaling.\",\n      \"evidence\": \"X-ray crystallography of IL-17RC ECD–IL-17F complex, SPR/ITC biophysical binding assays\",\n      \"pmids\": [\"32187518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional signaling through a 2:1 IL-17RC homodimeric receptor complex was not demonstrated in cells\", \"Structural basis of the ternary IL-17RA/IL-17RC/cytokine complex remains unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A non-immune role for IL-17RC was established in adipocytes, where γδ T cell-derived IL-17 signals through IL-17RC to induce TGFβ1, which in turn promotes sympathetic innervation of thermogenic fat; adipose-specific IL-17RC ablation causes obesity rescued by TGFβ1 restoration.\",\n      \"evidence\": \"Adipose-specific IL-17RC conditional knockout mice with TGFβ1 rescue, sympathetic innervation imaging, metabolic phenotyping\",\n      \"pmids\": [\"32076265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway operates through the canonical Act1-dependent mechanism was not tested\", \"Contribution of IL-17A vs IL-17F to adipocyte signaling was not distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional rescue of a novel homozygous IL17RC duplication variant in patient fibroblasts confirmed that AR IL-17RC loss-of-function is the genetic cause of chronic mucocutaneous candidiasis, reinforcing the human genetic evidence.\",\n      \"evidence\": \"Wild-type IL17RC complementation of SV40-immortalized patient fibroblasts with flow cytometry, qPCR, immunoblotting, and RNA-seq\",\n      \"pmids\": [\"38129603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype–phenotype correlation across partial vs complete IL-17RC deficiency is still limited to few families\", \"Broader immune phenotyping beyond CMC not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether IL-17RC homodimeric (2:1) complexes signal independently of IL-17RA in physiological contexts, the structural basis of the intracellular SEFIR–Act1 interaction, and the full spectrum of tissue-specific IL-17RC functions beyond immunity and adipose thermogenesis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for the IL-17RC intracellular domain or its complex with Act1\", \"Functional significance of multiple IL-17RC splice isoforms in vivo is unknown\", \"Whether IL-17RC participates in signaling by other IL-17 family members beyond IL-17A/F remains untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL17RA\", \"ACT1\", \"IL17A\", \"IL17F\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error in the pathway field — I used a GO term instead of a Reactome ID. Let me correct that.\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-17RC is a transmembrane cytokine receptor subunit essential for cellular responses to IL-17A, IL-17F, and IL-17A/F heterodimers, but dispensable for IL-17E (IL-25) signaling [PMID:17911633, PMID:25918342]. Upon ligand engagement, IL-17A induces recruitment of IL-17RC to IL-17RA to form a signaling-competent heteromeric complex; the cytoplasmic SEFIR domain and an extended downstream sequence of IL-17RC directly engage the adaptor/E3 ubiquitin ligase Act1 to initiate downstream signaling, while a 2:1 IL-17RC:IL-17F stoichiometry revealed by crystal structure demonstrates that IL-17RC can also occupy both binding sites on the cytokine homodimer independently of IL-17RA [PMID:20231694, PMID:20554964, PMID:32187518]. Beyond canonical immune signaling—where IL-17RC is required for mucocutaneous antifungal defense against Candida albicans—IL-17RC in adipocytes transduces γδ T cell-derived IL-17 signals to drive TGFβ1 expression, thereby promoting sympathetic innervation of thermogenic adipose tissue [PMID:20554964, PMID:32076265]. Autosomal-recessive IL-17RC deficiency causes chronic mucocutaneous candidiasis in humans [PMID:25918342, PMID:38129603].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing IL-17RC as a high-affinity receptor for both IL-17A and IL-17F resolved which receptor subunit directly engages these cytokines and showed that soluble IL-17RC can block both ligands, defining IL-17RC as a potential therapeutic target.\",\n      \"evidence\": \"Direct ligand-binding assays and soluble receptor antagonism with signaling inhibition readouts\",\n      \"pmids\": [\"17911633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the receptor complex was unknown\", \"Whether IL-17RC signals independently of IL-17RA was not addressed\", \"Intracellular signaling domains required for transduction were not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that both IL-17RA and IL-17RC are required for IL-17A-induced chemokine and IL-6 production in synoviocytes established that neither receptor alone is sufficient, implying obligate hetero-receptor signaling.\",\n      \"evidence\": \"siRNA knockdown of IL-17RA and IL-17RC individually and in combination in human synoviocytes with ELISA readout\",\n      \"pmids\": [\"18097068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of receptor cooperation was not defined\", \"Physical association of the two receptors was not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic deletion and structure-function analysis revealed that IL-17RC does not pre-associate with IL-17RA but is recruited upon IL-17A binding; the SEFIR domain plus an extended downstream cytoplasmic sequence directly engages the phosphorylated form of the adaptor Act1, establishing the core intracellular signaling mechanism.\",\n      \"evidence\": \"Il-17rc knockout mice, IL-17RC deletion mutant reconstitution in IL-17RC−/− fibroblasts, co-immunoprecipitation with Act1, oral candidiasis model, EAE disease model\",\n      \"pmids\": [\"20231694\", \"20554964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the IL-17RC–Act1 SEFIR–SEFIR interaction was not resolved\", \"How glycosylation of IL-17RA isoforms affects complex assembly remained unclear\", \"Whether IL-17RC has signaling capacity independent of IL-17RA was not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Human autosomal-recessive IL-17RC deficiency proved that IL-17RC is specifically required for IL-17A and IL-17F signaling (but not IL-17E) and is essential for mucocutaneous antifungal immunity, linking the receptor to chronic mucocutaneous candidiasis.\",\n      \"evidence\": \"Homozygous loss-of-function patient genetics with flow cytometry and cellular signaling assays in patient-derived cells across multiple kindreds\",\n      \"pmids\": [\"25918342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual IL-17 signaling via alternative receptors was not excluded in all tissues\", \"Whether partial IL-17RC deficiency produces an intermediate phenotype was not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"IL-17RC was placed upstream of the ubiquitin-editing enzyme A20 and JNK isoform-specific signaling in tumor cells, showing that loss of IL-17RC causes aberrant JNK activation correctable by A20 reconstitution, and separately, FSTL-1 was identified as a transcriptional regulator of IL-17RC expression in bone marrow stromal cells.\",\n      \"evidence\": \"siRNA knockdown and A20 reconstitution in melanoma/carcinoma lines; FSTL-1 suppression with surface protein expression and cytokine assays in stromal cells\",\n      \"pmids\": [\"28562353\", \"28377613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between IL-17RC signaling and A20 regulation was not shown\", \"FSTL-1 transcriptional control of IL17RC was demonstrated in one cell type only\", \"Relevance of IL-17RC–A20–JNK axis in non-tumor physiology not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The crystal structure of IL-17RC extracellular domain bound to IL-17F revealed a symmetrical 2:1 stoichiometry where two IL-17RC molecules occupy both binding sites on the cytokine homodimer, competing with IL-17RA and raising the possibility of IL-17RA-independent signaling.\",\n      \"evidence\": \"X-ray crystallography of IL-17RC ECD–IL-17F complex, SPR/ITC biophysical binding assays\",\n      \"pmids\": [\"32187518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional signaling through a 2:1 IL-17RC homodimeric receptor complex was not demonstrated in cells\", \"Structural basis of the ternary IL-17RA/IL-17RC/cytokine complex remains unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A non-immune role for IL-17RC was established in adipocytes, where γδ T cell-derived IL-17 signals through IL-17RC to induce TGFβ1, which in turn promotes sympathetic innervation of thermogenic fat; adipose-specific IL-17RC ablation causes obesity rescued by TGFβ1 restoration.\",\n      \"evidence\": \"Adipose-specific IL-17RC conditional knockout mice with TGFβ1 rescue, sympathetic innervation imaging, metabolic phenotyping\",\n      \"pmids\": [\"32076265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway operates through the canonical Act1-dependent mechanism was not tested\", \"Contribution of IL-17A vs IL-17F to adipocyte signaling was not distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional rescue of a novel homozygous IL17RC duplication variant in patient fibroblasts confirmed that AR IL-17RC loss-of-function is the genetic cause of chronic mucocutaneous candidiasis, reinforcing the human genetic evidence.\",\n      \"evidence\": \"Wild-type IL17RC complementation of SV40-immortalized patient fibroblasts with flow cytometry, qPCR, immunoblotting, and RNA-seq\",\n      \"pmids\": [\"38129603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype–phenotype correlation across partial vs complete IL-17RC deficiency is still limited to few families\", \"Broader immune phenotyping beyond CMC not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether IL-17RC homodimeric (2:1) complexes signal independently of IL-17RA in physiological contexts, the structural basis of the intracellular SEFIR–Act1 interaction, and the full spectrum of tissue-specific IL-17RC functions beyond immunity and adipose thermogenesis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for the IL-17RC intracellular domain or its complex with Act1\", \"Functional significance of multiple IL-17RC splice isoforms in vivo is unknown\", \"Whether IL-17RC participates in signaling by other IL-17 family members beyond IL-17A/F remains untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL17RA\", \"TRAF3IP2\", \"IL17A\", \"IL17F\"],\n    \"other_free_text\": []\n  }\n}\n```"}