{"gene":"IL17RC","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2007,"finding":"IL-17RC binds both IL-17A and IL-17F with high affinity and functions as a receptor for both cytokines; a soluble form of IL-17RC blocks binding of both IL-17A and IL-17F and inhibits their signaling.","method":"Binding assays, soluble receptor antagonism experiments, signaling inhibition assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding and functional blockade demonstrated, widely replicated across subsequent studies","pmids":["17911633"],"is_preprint":false},{"year":2010,"finding":"IL-17RC does not preassociate with IL-17RA on the cell surface; instead, IL-17A induces formation of an IL-17RC/IL-17RA complex. This ligand-induced complex formation is not dependent on the intracellular SEFIR domain of IL-17RC, but the SEFIR domain is essential for IL-17A signal transduction. IL-17RC is absolutely required for signaling by IL-17A, IL-17F, and IL-17A/F heterodimers both in vitro and in vivo.","method":"Il-17rc-deficient (knockout) mice, cell surface co-association assays, in vitro signaling assays, EAE disease model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular and in vivo phenotype, multiple orthogonal methods, replicated across labs","pmids":["20231694"],"is_preprint":false},{"year":2010,"finding":"The IL-17RC cytoplasmic tail contains a SEFIR domain that is necessary but not sufficient for IL-17-dependent signaling; an additional sequence downstream of the SEFIR (extended SEFIR) is also required. IL-17RC inducibly associates with a specific glycosylated isoform of IL-17RA independently of its own cytoplasmic tail. 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.","method":"IL-17RC deletion mutant panel in IL-17RC−/− fibroblasts (functional reconstitution), Co-IP/pulldown for Act1 interaction, target gene expression assays (IL-6, lipocalin-2)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstitution with deletion mutants, direct co-IP for Act1, multiple orthogonal methods in single rigorous study","pmids":["20554964"],"is_preprint":false},{"year":2015,"finding":"Complete autosomal-recessive IL-17RC deficiency abolishes cellular responses to IL-17A and IL-17F homo- and heterodimers but leaves IL-17E (IL-25) responses intact, establishing that IL-17RC is specifically required for IL-17A/F signaling and is essential for mucocutaneous immunity to Candida albicans.","method":"Primary cells from patients with homozygous nonsense alleles preventing IL-17RC surface expression; cytokine stimulation/response assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — natural loss-of-function human genetics with functional cellular validation across three 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 a symmetrical 2:1 (receptor:cytokine) complex, in which two IL-17RC molecules bind one IL-17F homodimer. IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC as shown by biophysical techniques, suggesting the possibility of IL-17RA-independent IL-17 signaling through IL-17RC.","method":"X-ray crystallography (crystal structure), biophysical binding assays (SPR/ITC)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biophysical validation in one rigorous study","pmids":["32187518"],"is_preprint":false},{"year":2020,"finding":"IL-17RC signaling in adipocytes is required for TGFβ1 expression, which promotes sympathetic innervation of thermogenic adipose tissue. Adipose-tissue-specific ablation of IL-17RC reduces TGFβ1 in adipocytes, impairs local sympathetic innervation, and causes obesity and defective thermogenesis; innervation is fully rescued by restoring TGFβ1 expression. γδ T cells drive this process upstream of IL-17RC.","method":"Adipose-tissue-specific IL-17RC knockout mice, TGFβ1 rescue experiments, sympathetic innervation quantification, metabolic phenotyping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular and metabolic phenotype, rescue experiment, multiple orthogonal readouts","pmids":["32076265"],"is_preprint":false},{"year":2008,"finding":"Both IL-17RA and IL-17RC are required for IL-17A-induced IL-6, IL-8, and CCL-20 secretion in rheumatoid synoviocytes; siRNA knockdown of either receptor alone nearly abrogates IL-17A-mediated IL-6 secretion, and combined knockdown is needed to suppress IL-17A+TNF-α-induced responses.","method":"siRNA knockdown of IL-17RA and IL-17RC individually and in combination; ELISA for cytokine secretion; microarray gene expression","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with cytokine readout, single lab, two orthogonal methods (siRNA + extracellular blockade)","pmids":["18097068"],"is_preprint":false},{"year":2007,"finding":"Inhibition of either IL-17RA or IL-17RC expression via siRNA leads to near-complete abrogation of IL-17A-mediated c-Jun and p65 NF-κB activation and IL-8 secretion in gastric adenocarcinoma cells, indicating both receptors are required for IL-17A signaling.","method":"siRNA knockdown, Western blot, transcription factor binding assays, ELISA","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with mechanistic pathway readout, single lab, single cell line","pmids":["17644350"],"is_preprint":false},{"year":2017,"finding":"Follistatin-like protein 1 (FSTL-1) is necessary for Il17rc gene transcription and IL-17RC surface protein expression in bone marrow stromal cells; loss of FSTL-1 reduces IL-17RC levels and abolishes IL-17-dependent IL-6 and G-CSF production, identifying FSTL-1 as an upstream regulator of IL-17RC expression.","method":"In vitro FSTL-1 suppression (bone marrow stromal cells), microarray, surface protein expression assays, cytokine production assays","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular and functional readout, two orthogonal methods (microarray + protein expression + cytokine assay), single lab","pmids":["28377613"],"is_preprint":false},{"year":2017,"finding":"IL-17RC knockdown in B16 melanoma and 4T1 carcinoma cells diminishes baseline A20 (ubiquitin-editing enzyme) levels and causes aberrant differential upregulation of JNK1 or JNK2, respectively, leading to reciprocal changes in tumor-specific proliferation. Reconstitution with full-length A20 (but not a truncation mutant) reverses aberrant JNK activity and restores normal proliferation, establishing an IL-17RC–A20–JNK axis in tumor cells.","method":"shRNA knockdown of IL-17RC, A20 reconstitution with full-length and truncation mutants, Western blot for JNK isoforms, in vitro and in vivo tumor proliferation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with rescue by full-length vs mutant A20, in vitro and in vivo readouts, single lab","pmids":["28562353"],"is_preprint":false},{"year":2019,"finding":"A missense mutation (rs199772854A) in IL17RC overexpresses the protein and significantly increases expression of TRAF6 and NF-κB in osteoblasts, promoting osteogenic differentiation, suggesting IL-17RC signals through the IL-17/TRAF6/NF-κB axis to drive ectopic osteogenesis.","method":"Overexpression of mutant and WT IL17RC in 3T3-E1 osteoblasts, RT-qPCR, Western blot for osteogenic markers and NF-κB pathway components","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression in a cell line, limited mechanistic depth, no epistasis or rescue","pmids":["30864693"],"is_preprint":false},{"year":2022,"finding":"Recombinant IL-17A induces expression of IL-17RC in gastric cancer cells (AGS), leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels; inhibition of NOX1 attenuates IL-17A-mediated cancer cell growth, ROS generation, and cancer stem cell stemness, placing IL-17RC upstream of an NF-κB/NOX1 axis.","method":"Recombinant cytokine stimulation, pharmacological NOX1 inhibition, in vitro growth and sphere formation assays, IL-17A KO mice with H. pylori/MNU-induced GC model","journal":"Gastric cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway dissection with pharmacological inhibitor and in vivo KO model, single lab","pmids":["36125689"],"is_preprint":false},{"year":2023,"finding":"A novel homozygous duplication variant in IL17RC (exon 13, causing frameshift and premature stop p.D457Afs*16) is loss-of-function; patient SV40-immortalized fibroblasts lack response to IL-17A, and this defect is restored by introducing wild-type IL17RC, confirming the receptor's essential role in IL-17A signal transduction.","method":"Flow cytometry, qPCR, RNA-sequencing, immunoblotting, IL17RC-knockout cell line complementation with WT IL17RC","journal":"Journal of clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional rescue with WT protein in patient-derived cells, multiple orthogonal methods, single lab","pmids":["38129603"],"is_preprint":false},{"year":2017,"finding":"UVB irradiation downregulates IL-17RA and IL-17RC expression on human dermal fibroblasts through TGF-β1/Smad3 signaling, thereby inhibiting IL-17A/TNF-α-induced IL-6, IL-8, and CXCL-1 production.","method":"UVB irradiation of cultured fibroblasts, TGF-β1 treatment, Western blot, qPCR, ELISA, flow cytometry for receptor expression","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative pathway assignment, no epistasis or rescue experiment specifically for IL-17RC","pmids":["28217129"],"is_preprint":false},{"year":2026,"finding":"IL-17RC signaling in intestinal epithelial cells maintains intestinal barrier integrity and controls microbiota composition; loss of IL-17RC in intestinal epithelial cells alters the microbiota, enhances perivascular innervation and aortic inflammation, and augments atherosclerosis. Cell-autonomous IL-17RC signaling in sympathetic neurons is also required, as neuron-specific IL-17RC ablation protects mice from microbiota-driven atherosclerosis.","method":"Cell-type-specific IL-17RC knockout mice (intestinal epithelial and sympathetic neuron), microbiota analysis, chemical denervation, γδ T cell blockade, disease progression quantification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in two cell types with defined mechanistic and phenotypic readouts, preprint (not yet peer-reviewed)","pmids":["41959117"],"is_preprint":true}],"current_model":"IL-17RC is a transmembrane receptor subunit that binds IL-17A and IL-17F (forming a symmetrical 2:1 extracellular complex) and is obligatorily recruited to IL-17RA upon ligand stimulation to form a functional signaling complex; its cytoplasmic extended SEFIR domain directly engages the adaptor/E3 ligase Act1, activating NF-κB and MAPK pathways, while cell-type-specific IL-17RC signaling also drives TGFβ1-dependent sympathetic innervation of adipose tissue and controls intestinal barrier homeostasis, and complete loss of IL-17RC in humans abolishes IL-17A/F responses and causes chronic mucocutaneous candidiasis."},"narrative":{"mechanistic_narrative":"IL-17RC is a transmembrane receptor subunit that serves as an obligate signaling component for the IL-17A and IL-17F cytokines, binding both with high affinity while sparing IL-17E/IL-25 responses [PMID:17911633, PMID:25918342]. Rather than preassociating with its co-receptor, IL-17RC is recruited to a specific glycosylated isoform of IL-17RA in a ligand-induced manner, and structurally two IL-17RC molecules engage one IL-17F homodimer in a symmetrical 2:1 extracellular complex [PMID:20231694, PMID:32187518]. Signal transduction depends on the cytoplasmic SEFIR domain together with an additional downstream \"extended SEFIR\" segment, which directly recruits the adaptor/E3 ligase Act1 to drive NF-κB and MAPK (c-Jun) activation and the secretion of IL-6, IL-8, and CCL-20 [PMID:20554964, PMID:17644350]. Both IL-17RA and IL-17RC are jointly required for these inflammatory responses in target cells [PMID:18097068, PMID:17644350]. Beyond classical inflammation, cell-type-specific IL-17RC signaling drives TGFβ1-dependent sympathetic innervation of thermogenic adipose tissue and controls intestinal epithelial barrier and microbiota homeostasis [PMID:32076265, PMID:41959117]. In humans, complete autosomal-recessive loss of IL-17RC abolishes IL-17A/F responses and causes chronic mucocutaneous candidiasis [PMID:25918342, PMID:38129603].","teleology":[{"year":2007,"claim":"Established that IL-17RC is a functional receptor that binds both IL-17A and IL-17F, defining its ligand specificity and antagonizability.","evidence":"Binding assays and soluble-receptor blockade of IL-17A/F signaling","pmids":["17911633"],"confidence":"High","gaps":["Did not resolve whether IL-17RC acts alone or requires a co-receptor","No stoichiometry or structural detail of the binding interface"]},{"year":2007,"claim":"Showed in human cells that both IL-17RA and IL-17RC are jointly required for IL-17A-driven NF-κB/c-Jun activation, indicating a shared receptor complex.","evidence":"siRNA knockdown with transcription-factor and IL-8 readouts in gastric adenocarcinoma cells","pmids":["17644350"],"confidence":"Medium","gaps":["Single cell line, single lab","Did not define how the two receptors physically assemble"]},{"year":2008,"claim":"Confirmed the requirement for both receptors in a disease-relevant primary cell type, generalizing the IL-17RA/IL-17RC dependency.","evidence":"Individual and combined siRNA knockdown with cytokine ELISA in rheumatoid synoviocytes","pmids":["18097068"],"confidence":"Medium","gaps":["Correlative receptor requirement without direct complex characterization"]},{"year":2010,"claim":"Resolved how the receptor complex forms and signals: ligand-induced (not preassembled) IL-17RC/IL-17RA recruitment, with the SEFIR domain dispensable for assembly but essential for signaling, and demonstrated absolute requirement in vivo.","evidence":"Il-17rc knockout mice, surface co-association assays, in vitro signaling, and EAE model","pmids":["20231694"],"confidence":"High","gaps":["Did not identify the intracellular effectors engaged by the SEFIR domain"]},{"year":2010,"claim":"Defined the intracellular signaling mechanism by mapping an extended SEFIR region required for function and showing direct recruitment of Act1, linking the receptor to downstream pathway activation.","evidence":"Deletion-mutant reconstitution in IL-17RC-deficient fibroblasts, Act1 Co-IP, and target gene assays","pmids":["20554964"],"confidence":"High","gaps":["Structural basis of the SEFIR–Act1 interaction not resolved","Dynamics of Act1 phosphorylation-dependent engagement not detailed"]},{"year":2015,"claim":"Demonstrated through human genetics that IL-17RC is non-redundantly required for IL-17A/F (but not IL-17E) immunity, causally linking its loss to mucocutaneous candidiasis.","evidence":"Primary cells from kindreds with homozygous nonsense alleles and cytokine response assays","pmids":["25918342"],"confidence":"High","gaps":["Does not address tissue-specific or non-immune functions of the receptor"]},{"year":2017,"claim":"Identified upstream control of IL-17RC abundance, showing FSTL-1 is needed for Il17rc transcription and surface expression and thus for downstream IL-17 responses.","evidence":"FSTL-1 suppression in bone marrow stromal cells with surface expression and cytokine readouts","pmids":["28377613"],"confidence":"Medium","gaps":["Mechanism by which FSTL-1 drives Il17rc transcription not defined","Single lab and cell context"]},{"year":2017,"claim":"Implicated IL-17RC in tumor-cell-intrinsic signaling through an A20–JNK axis distinct from canonical inflammatory output.","evidence":"shRNA knockdown with A20 full-length vs truncation rescue and JNK isoform analysis in melanoma/carcinoma cells","pmids":["28562353"],"confidence":"Medium","gaps":["How IL-17RC controls baseline A20 levels is unresolved","Ligand dependence of this axis not established"]},{"year":2020,"claim":"Provided the structural framework for ligand recognition, revealing a symmetrical 2:1 IL-17RC:cytokine complex and raising the prospect of IL-17RA-independent signaling.","evidence":"X-ray crystallography of the IL-17RC ectodomain with IL-17F plus SPR/ITC biophysics","pmids":["32187518"],"confidence":"High","gaps":["Functional existence of IL-17RA-independent signaling not demonstrated","No structure of the full ternary receptor complex"]},{"year":2020,"claim":"Uncovered a non-immune tissue function: adipocyte IL-17RC drives TGFβ1-dependent sympathetic innervation governing thermogenesis and body weight.","evidence":"Adipose-specific IL-17RC knockout mice with TGFβ1 rescue and metabolic phenotyping","pmids":["32076265"],"confidence":"High","gaps":["Intracellular signaling linking IL-17RC to TGFβ1 induction not mapped","Whether Act1 mediates this axis is untested"]},{"year":2022,"claim":"Extended IL-17RC's tumor role to an NF-κB/NOX1 axis controlling ROS, growth, and stemness in gastric cancer.","evidence":"Recombinant IL-17A stimulation, pharmacological NOX1 inhibition, and in vivo gastric cancer model","pmids":["36125689"],"confidence":"Medium","gaps":["Direct mechanistic coupling of IL-17RC to NOX1 not established","Single lab"]},{"year":2023,"claim":"Reaffirmed the receptor's essential role via a new loss-of-function patient variant rescued by wild-type IL17RC, providing causal validation in patient-derived cells.","evidence":"Patient SV40 fibroblasts with frameshift variant and WT IL17RC complementation across multiple assays","pmids":["38129603"],"confidence":"High","gaps":["Does not add new mechanistic detail beyond confirming signaling requirement"]},{"year":2026,"claim":"Revealed cell-autonomous IL-17RC functions in intestinal epithelium and sympathetic neurons that control microbiota, vascular inflammation, and atherosclerosis.","evidence":"Cell-type-specific IL-17RC knockout mice, microbiota analysis, chemical denervation, and γδ T cell blockade (preprint)","pmids":["41959117"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Intracellular effectors in neurons and epithelium not defined"]},{"year":null,"claim":"Whether IL-17RC can signal independently of IL-17RA in vivo, and what intracellular machinery couples it to its non-immune (TGFβ1, innervation, microbiota) outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No demonstration of IL-17RA-independent signaling despite structural plausibility","Effector pathway downstream of IL-17RC in non-immune tissues unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,7]}],"complexes":["IL-17RA/IL-17RC receptor complex"],"partners":["IL17RA","IL17A","IL17F","TRAF3IP2"],"other_free_text":[]}},"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":283,"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":151,"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":151,"is_preprint":false},{"pmid":"23177625","id":"PMC_23177625","title":"Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.","date":"2012","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23177625","citation_count":144,"is_preprint":false},{"pmid":"20231694","id":"PMC_20231694","title":"IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20231694","citation_count":123,"is_preprint":false},{"pmid":"18097068","id":"PMC_18097068","title":"IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18097068","citation_count":111,"is_preprint":false},{"pmid":"20554964","id":"PMC_20554964","title":"IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20554964","citation_count":103,"is_preprint":false},{"pmid":"20012905","id":"PMC_20012905","title":"IL-17RC: a partner in IL-17 signaling and beyond.","date":"2009","source":"Seminars in immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/20012905","citation_count":88,"is_preprint":false},{"pmid":"21109515","id":"PMC_21109515","title":"IL-17A- versus IL-17F-induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in rheumatoid synoviocytes.","date":"2010","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21109515","citation_count":69,"is_preprint":false},{"pmid":"32187518","id":"PMC_32187518","title":"Structural Analysis Reveals that the Cytokine IL-17F Forms a Homodimeric Complex with Receptor IL-17RC to Drive IL-17RA-Independent Signaling.","date":"2020","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/32187518","citation_count":65,"is_preprint":false},{"pmid":"20045440","id":"PMC_20045440","title":"IL-17A suppresses the expression of bone resorption-related proteinases and osteoclast differentiation via IL-17RA or IL-17RC receptors in RAW264.7 cells.","date":"2010","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/20045440","citation_count":58,"is_preprint":false},{"pmid":"17644350","id":"PMC_17644350","title":"IL-17A versus IL-17F induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in AGS gastric adenocarcinoma cells.","date":"2007","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/17644350","citation_count":54,"is_preprint":false},{"pmid":"24373284","id":"PMC_24373284","title":"Hypomethylation of the IL17RC promoter in peripheral blood leukocytes is not a hallmark of age-related macular degeneration.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24373284","citation_count":42,"is_preprint":false},{"pmid":"29584788","id":"PMC_29584788","title":"IL-17A, IL-17RC polymorphisms and IL17 plasma levels in Tunisian patients with rheumatoid arthritis.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29584788","citation_count":33,"is_preprint":false},{"pmid":"17603628","id":"PMC_17603628","title":"Differential expression of IL-17RC isoforms in androgen-dependent and androgen-independent prostate cancers.","date":"2007","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17603628","citation_count":28,"is_preprint":false},{"pmid":"36125689","id":"PMC_36125689","title":"IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC.","date":"2022","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/36125689","citation_count":27,"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":27,"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":25,"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":3,"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":"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":"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":"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":"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":20573,"output_tokens":3879,"usd":0.059952,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11705,"output_tokens":3690,"usd":0.075387,"stage2_stop_reason":"end_turn"},"total_usd":0.135339,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-17RC binds both IL-17A and IL-17F with high affinity and functions as a receptor for both cytokines; a soluble form of IL-17RC blocks binding of both IL-17A and IL-17F and inhibits their signaling.\",\n      \"method\": \"Binding assays, soluble receptor antagonism experiments, signaling inhibition assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding and functional blockade demonstrated, widely replicated across subsequent studies\",\n      \"pmids\": [\"17911633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RC does not preassociate with IL-17RA on the cell surface; instead, IL-17A induces formation of an IL-17RC/IL-17RA complex. This ligand-induced complex formation is not dependent on the intracellular SEFIR domain of IL-17RC, but the SEFIR domain is essential for IL-17A signal transduction. IL-17RC is absolutely required for signaling by IL-17A, IL-17F, and IL-17A/F heterodimers both in vitro and in vivo.\",\n      \"method\": \"Il-17rc-deficient (knockout) mice, cell surface co-association assays, in vitro signaling assays, EAE disease model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular and in vivo phenotype, multiple orthogonal methods, replicated across labs\",\n      \"pmids\": [\"20231694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The IL-17RC cytoplasmic tail contains a SEFIR domain that is necessary but not sufficient for IL-17-dependent signaling; an additional sequence downstream of the SEFIR (extended SEFIR) is also required. IL-17RC inducibly associates with a specific glycosylated isoform of IL-17RA independently of its own cytoplasmic tail. 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.\",\n      \"method\": \"IL-17RC deletion mutant panel in IL-17RC−/− fibroblasts (functional reconstitution), Co-IP/pulldown for Act1 interaction, target gene expression assays (IL-6, lipocalin-2)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstitution with deletion mutants, direct co-IP for Act1, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"20554964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Complete autosomal-recessive IL-17RC deficiency abolishes cellular responses to IL-17A and IL-17F homo- and heterodimers but leaves IL-17E (IL-25) responses intact, establishing that IL-17RC is specifically required for IL-17A/F signaling and is essential for mucocutaneous immunity to Candida albicans.\",\n      \"method\": \"Primary cells from patients with homozygous nonsense alleles preventing IL-17RC surface expression; cytokine stimulation/response assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — natural loss-of-function human genetics with functional cellular validation across three 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 a symmetrical 2:1 (receptor:cytokine) complex, in which two IL-17RC molecules bind one IL-17F homodimer. IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC as shown by biophysical techniques, suggesting the possibility of IL-17RA-independent IL-17 signaling through IL-17RC.\",\n      \"method\": \"X-ray crystallography (crystal structure), biophysical binding assays (SPR/ITC)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biophysical validation in one rigorous study\",\n      \"pmids\": [\"32187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17RC signaling in adipocytes is required for TGFβ1 expression, which promotes sympathetic innervation of thermogenic adipose tissue. Adipose-tissue-specific ablation of IL-17RC reduces TGFβ1 in adipocytes, impairs local sympathetic innervation, and causes obesity and defective thermogenesis; innervation is fully rescued by restoring TGFβ1 expression. γδ T cells drive this process upstream of IL-17RC.\",\n      \"method\": \"Adipose-tissue-specific IL-17RC knockout mice, TGFβ1 rescue experiments, sympathetic innervation quantification, metabolic phenotyping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular and metabolic phenotype, rescue experiment, multiple orthogonal readouts\",\n      \"pmids\": [\"32076265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Both IL-17RA and IL-17RC are required for IL-17A-induced IL-6, IL-8, and CCL-20 secretion in rheumatoid synoviocytes; siRNA knockdown of either receptor alone nearly abrogates IL-17A-mediated IL-6 secretion, and combined knockdown is needed to suppress IL-17A+TNF-α-induced responses.\",\n      \"method\": \"siRNA knockdown of IL-17RA and IL-17RC individually and in combination; ELISA for cytokine secretion; microarray gene expression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with cytokine readout, single lab, two orthogonal methods (siRNA + extracellular blockade)\",\n      \"pmids\": [\"18097068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Inhibition of either IL-17RA or IL-17RC expression via siRNA leads to near-complete abrogation of IL-17A-mediated c-Jun and p65 NF-κB activation and IL-8 secretion in gastric adenocarcinoma cells, indicating both receptors are required for IL-17A signaling.\",\n      \"method\": \"siRNA knockdown, Western blot, transcription factor binding assays, ELISA\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with mechanistic pathway readout, single lab, single cell line\",\n      \"pmids\": [\"17644350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Follistatin-like protein 1 (FSTL-1) is necessary for Il17rc gene transcription and IL-17RC surface protein expression in bone marrow stromal cells; loss of FSTL-1 reduces IL-17RC levels and abolishes IL-17-dependent IL-6 and G-CSF production, identifying FSTL-1 as an upstream regulator of IL-17RC expression.\",\n      \"method\": \"In vitro FSTL-1 suppression (bone marrow stromal cells), microarray, surface protein expression assays, cytokine production assays\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular and functional readout, two orthogonal methods (microarray + protein expression + 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 diminishes baseline A20 (ubiquitin-editing enzyme) levels and causes aberrant differential upregulation of JNK1 or JNK2, respectively, leading to reciprocal changes in tumor-specific proliferation. Reconstitution with full-length A20 (but not a truncation mutant) reverses aberrant JNK activity and restores normal proliferation, establishing an IL-17RC–A20–JNK axis in tumor cells.\",\n      \"method\": \"shRNA knockdown of IL-17RC, A20 reconstitution with full-length and truncation mutants, Western blot for JNK isoforms, in vitro and in vivo tumor proliferation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with rescue by full-length vs mutant A20, in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"28562353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A missense mutation (rs199772854A) in IL17RC overexpresses the protein and significantly increases expression of TRAF6 and NF-κB in osteoblasts, promoting osteogenic differentiation, suggesting IL-17RC signals through the IL-17/TRAF6/NF-κB axis to drive ectopic osteogenesis.\",\n      \"method\": \"Overexpression of mutant and WT IL17RC in 3T3-E1 osteoblasts, RT-qPCR, Western blot for osteogenic markers and NF-κB pathway components\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression in a cell line, limited mechanistic depth, no epistasis or rescue\",\n      \"pmids\": [\"30864693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Recombinant IL-17A induces expression of IL-17RC in gastric cancer cells (AGS), leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels; inhibition of NOX1 attenuates IL-17A-mediated cancer cell growth, ROS generation, and cancer stem cell stemness, placing IL-17RC upstream of an NF-κB/NOX1 axis.\",\n      \"method\": \"Recombinant cytokine stimulation, pharmacological NOX1 inhibition, in vitro growth and sphere formation assays, IL-17A KO mice with H. pylori/MNU-induced GC model\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway dissection with pharmacological inhibitor and in vivo KO model, single lab\",\n      \"pmids\": [\"36125689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A novel homozygous duplication variant in IL17RC (exon 13, causing frameshift and premature stop p.D457Afs*16) is loss-of-function; patient SV40-immortalized fibroblasts lack response to IL-17A, and this defect is restored by introducing wild-type IL17RC, confirming the receptor's essential role in IL-17A signal transduction.\",\n      \"method\": \"Flow cytometry, qPCR, RNA-sequencing, immunoblotting, IL17RC-knockout cell line complementation with WT IL17RC\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue with WT protein in patient-derived cells, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38129603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UVB irradiation downregulates IL-17RA and IL-17RC expression on human dermal fibroblasts through TGF-β1/Smad3 signaling, thereby inhibiting IL-17A/TNF-α-induced IL-6, IL-8, and CXCL-1 production.\",\n      \"method\": \"UVB irradiation of cultured fibroblasts, TGF-β1 treatment, Western blot, qPCR, ELISA, flow cytometry for receptor expression\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative pathway assignment, no epistasis or rescue experiment specifically for IL-17RC\",\n      \"pmids\": [\"28217129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IL-17RC signaling in intestinal epithelial cells maintains intestinal barrier integrity and controls microbiota composition; loss of IL-17RC in intestinal epithelial cells alters the microbiota, enhances perivascular innervation and aortic inflammation, and augments atherosclerosis. Cell-autonomous IL-17RC signaling in sympathetic neurons is also required, as neuron-specific IL-17RC ablation protects mice from microbiota-driven atherosclerosis.\",\n      \"method\": \"Cell-type-specific IL-17RC knockout mice (intestinal epithelial and sympathetic neuron), microbiota analysis, chemical denervation, γδ T cell blockade, disease progression quantification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in two cell types with defined mechanistic and phenotypic readouts, preprint (not yet peer-reviewed)\",\n      \"pmids\": [\"41959117\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL-17RC is a transmembrane receptor subunit that binds IL-17A and IL-17F (forming a symmetrical 2:1 extracellular complex) and is obligatorily recruited to IL-17RA upon ligand stimulation to form a functional signaling complex; its cytoplasmic extended SEFIR domain directly engages the adaptor/E3 ligase Act1, activating NF-κB and MAPK pathways, while cell-type-specific IL-17RC signaling also drives TGFβ1-dependent sympathetic innervation of adipose tissue and controls intestinal barrier homeostasis, and complete loss of IL-17RC in humans abolishes IL-17A/F responses and causes chronic mucocutaneous candidiasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-17RC is a transmembrane receptor subunit that serves as an obligate signaling component for the IL-17A and IL-17F cytokines, binding both with high affinity while sparing IL-17E/IL-25 responses [#0, #3]. Rather than preassociating with its co-receptor, IL-17RC is recruited to a specific glycosylated isoform of IL-17RA in a ligand-induced manner, and structurally two IL-17RC molecules engage one IL-17F homodimer in a symmetrical 2:1 extracellular complex [#1, #4]. Signal transduction depends on the cytoplasmic SEFIR domain together with an additional downstream \\\"extended SEFIR\\\" segment, which directly recruits the adaptor/E3 ligase Act1 to drive NF-\\u03baB and MAPK (c-Jun) activation and the secretion of IL-6, IL-8, and CCL-20 [#2, #7]. Both IL-17RA and IL-17RC are jointly required for these inflammatory responses in target cells [#6, #7]. Beyond classical inflammation, cell-type-specific IL-17RC signaling drives TGF\\u03b21-dependent sympathetic innervation of thermogenic adipose tissue and controls intestinal epithelial barrier and microbiota homeostasis [#5, #14]. In humans, complete autosomal-recessive loss of IL-17RC abolishes IL-17A/F responses and causes chronic mucocutaneous candidiasis [#3, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that IL-17RC is a functional receptor that binds both IL-17A and IL-17F, defining its ligand specificity and antagonizability.\",\n      \"evidence\": \"Binding assays and soluble-receptor blockade of IL-17A/F signaling\",\n      \"pmids\": [\"17911633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether IL-17RC acts alone or requires a co-receptor\", \"No stoichiometry or structural detail of the binding interface\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed in human cells that both IL-17RA and IL-17RC are jointly required for IL-17A-driven NF-\\u03baB/c-Jun activation, indicating a shared receptor complex.\",\n      \"evidence\": \"siRNA knockdown with transcription-factor and IL-8 readouts in gastric adenocarcinoma cells\",\n      \"pmids\": [\"17644350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line, single lab\", \"Did not define how the two receptors physically assemble\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed the requirement for both receptors in a disease-relevant primary cell type, generalizing the IL-17RA/IL-17RC dependency.\",\n      \"evidence\": \"Individual and combined siRNA knockdown with cytokine ELISA in rheumatoid synoviocytes\",\n      \"pmids\": [\"18097068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative receptor requirement without direct complex characterization\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how the receptor complex forms and signals: ligand-induced (not preassembled) IL-17RC/IL-17RA recruitment, with the SEFIR domain dispensable for assembly but essential for signaling, and demonstrated absolute requirement in vivo.\",\n      \"evidence\": \"Il-17rc knockout mice, surface co-association assays, in vitro signaling, and EAE model\",\n      \"pmids\": [\"20231694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the intracellular effectors engaged by the SEFIR domain\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the intracellular signaling mechanism by mapping an extended SEFIR region required for function and showing direct recruitment of Act1, linking the receptor to downstream pathway activation.\",\n      \"evidence\": \"Deletion-mutant reconstitution in IL-17RC-deficient fibroblasts, Act1 Co-IP, and target gene assays\",\n      \"pmids\": [\"20554964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SEFIR\\u2013Act1 interaction not resolved\", \"Dynamics of Act1 phosphorylation-dependent engagement not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated through human genetics that IL-17RC is non-redundantly required for IL-17A/F (but not IL-17E) immunity, causally linking its loss to mucocutaneous candidiasis.\",\n      \"evidence\": \"Primary cells from kindreds with homozygous nonsense alleles and cytokine response assays\",\n      \"pmids\": [\"25918342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address tissue-specific or non-immune functions of the receptor\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified upstream control of IL-17RC abundance, showing FSTL-1 is needed for Il17rc transcription and surface expression and thus for downstream IL-17 responses.\",\n      \"evidence\": \"FSTL-1 suppression in bone marrow stromal cells with surface expression and cytokine readouts\",\n      \"pmids\": [\"28377613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FSTL-1 drives Il17rc transcription not defined\", \"Single lab and cell context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated IL-17RC in tumor-cell-intrinsic signaling through an A20\\u2013JNK axis distinct from canonical inflammatory output.\",\n      \"evidence\": \"shRNA knockdown with A20 full-length vs truncation rescue and JNK isoform analysis in melanoma/carcinoma cells\",\n      \"pmids\": [\"28562353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How IL-17RC controls baseline A20 levels is unresolved\", \"Ligand dependence of this axis not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural framework for ligand recognition, revealing a symmetrical 2:1 IL-17RC:cytokine complex and raising the prospect of IL-17RA-independent signaling.\",\n      \"evidence\": \"X-ray crystallography of the IL-17RC ectodomain with IL-17F plus SPR/ITC biophysics\",\n      \"pmids\": [\"32187518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional existence of IL-17RA-independent signaling not demonstrated\", \"No structure of the full ternary receptor complex\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a non-immune tissue function: adipocyte IL-17RC drives TGF\\u03b21-dependent sympathetic innervation governing thermogenesis and body weight.\",\n      \"evidence\": \"Adipose-specific IL-17RC knockout mice with TGF\\u03b21 rescue and metabolic phenotyping\",\n      \"pmids\": [\"32076265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling linking IL-17RC to TGF\\u03b21 induction not mapped\", \"Whether Act1 mediates this axis is untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended IL-17RC's tumor role to an NF-\\u03baB/NOX1 axis controlling ROS, growth, and stemness in gastric cancer.\",\n      \"evidence\": \"Recombinant IL-17A stimulation, pharmacological NOX1 inhibition, and in vivo gastric cancer model\",\n      \"pmids\": [\"36125689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic coupling of IL-17RC to NOX1 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reaffirmed the receptor's essential role via a new loss-of-function patient variant rescued by wild-type IL17RC, providing causal validation in patient-derived cells.\",\n      \"evidence\": \"Patient SV40 fibroblasts with frameshift variant and WT IL17RC complementation across multiple assays\",\n      \"pmids\": [\"38129603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not add new mechanistic detail beyond confirming signaling requirement\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed cell-autonomous IL-17RC functions in intestinal epithelium and sympathetic neurons that control microbiota, vascular inflammation, and atherosclerosis.\",\n      \"evidence\": \"Cell-type-specific IL-17RC knockout mice, microbiota analysis, chemical denervation, and \\u03b3\\u03b4 T cell blockade (preprint)\",\n      \"pmids\": [\"41959117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Intracellular effectors in neurons and epithelium not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether IL-17RC can signal independently of IL-17RA in vivo, and what intracellular machinery couples it to its non-immune (TGF\\u03b21, innervation, microbiota) outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of IL-17RA-independent signaling despite structural plausibility\", \"Effector pathway downstream of IL-17RC in non-immune tissues unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 7]}\n    ],\n    \"complexes\": [\"IL-17RA/IL-17RC receptor complex\"],\n    \"partners\": [\"IL17RA\", \"IL17A\", \"IL17F\", \"TRAF3IP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}