Affinage

IL17RC

Interleukin-17 receptor C · UniProt Q8NAC3

Length
791 aa
Mass
86.2 kDa
Annotated
2026-06-10
38 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 High

    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

    PMID:17911633

    Open questions at the time
    • Did not resolve whether IL-17RC acts alone or requires a co-receptor
    • No stoichiometry or structural detail of the binding interface
  2. 2007 Medium

    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

    PMID:17644350

    Open questions at the time
    • Single cell line, single lab
    • Did not define how the two receptors physically assemble
  3. 2008 Medium

    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

    PMID:18097068

    Open questions at the time
    • Correlative receptor requirement without direct complex characterization
  4. 2010 High

    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

    PMID:20231694

    Open questions at the time
    • Did not identify the intracellular effectors engaged by the SEFIR domain
  5. 2010 High

    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

    PMID:20554964

    Open questions at the time
    • Structural basis of the SEFIR–Act1 interaction not resolved
    • Dynamics of Act1 phosphorylation-dependent engagement not detailed
  6. 2015 High

    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

    PMID:25918342

    Open questions at the time
    • Does not address tissue-specific or non-immune functions of the receptor
  7. 2017 Medium

    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

    PMID:28377613

    Open questions at the time
    • Mechanism by which FSTL-1 drives Il17rc transcription not defined
    • Single lab and cell context
  8. 2017 Medium

    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

    PMID:28562353

    Open questions at the time
    • How IL-17RC controls baseline A20 levels is unresolved
    • Ligand dependence of this axis not established
  9. 2020 High

    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

    PMID:32187518

    Open questions at the time
    • Functional existence of IL-17RA-independent signaling not demonstrated
    • No structure of the full ternary receptor complex
  10. 2020 High

    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

    PMID:32076265

    Open questions at the time
    • Intracellular signaling linking IL-17RC to TGFβ1 induction not mapped
    • Whether Act1 mediates this axis is untested
  11. 2022 Medium

    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

    PMID:36125689

    Open questions at the time
    • Direct mechanistic coupling of IL-17RC to NOX1 not established
    • Single lab
  12. 2023 High

    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

    PMID:38129603

    Open questions at the time
    • Does not add new mechanistic detail beyond confirming signaling requirement
  13. 2026 Medium

    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)

    PMID:41959117

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Intracellular effectors in neurons and epithelium not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No demonstration of IL-17RA-independent signaling despite structural plausibility
  • Effector pathway downstream of IL-17RC in non-immune tissues unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
IL17AIL17FIL17RATRAF3IP2
Complex memberships
IL-17RA/IL-17RC receptor complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. Binding assays, soluble receptor antagonism experiments, signaling inhibition assays Journal of immunology High 17911633
2010 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. Il-17rc-deficient (knockout) mice, cell surface co-association assays, in vitro signaling assays, EAE disease model Journal of immunology High 20231694
2010 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. 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 of immunology High 20554964
2015 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. Primary cells from patients with homozygous nonsense alleles preventing IL-17RC surface expression; cytokine stimulation/response assays The Journal of experimental medicine High 25918342
2020 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. X-ray crystallography (crystal structure), biophysical binding assays (SPR/ITC) Immunity High 32187518
2020 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. Adipose-tissue-specific IL-17RC knockout mice, TGFβ1 rescue experiments, sympathetic innervation quantification, metabolic phenotyping Nature High 32076265
2008 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. siRNA knockdown of IL-17RA and IL-17RC individually and in combination; ELISA for cytokine secretion; microarray gene expression Journal of immunology Medium 18097068
2007 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. siRNA knockdown, Western blot, transcription factor binding assays, ELISA Cytokine Medium 17644350
2017 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. In vitro FSTL-1 suppression (bone marrow stromal cells), microarray, surface protein expression assays, cytokine production assays Immunology and cell biology Medium 28377613
2017 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. 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 Oncotarget Medium 28562353
2019 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. Overexpression of mutant and WT IL17RC in 3T3-E1 osteoblasts, RT-qPCR, Western blot for osteogenic markers and NF-κB pathway components International journal of molecular medicine Low 30864693
2022 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. Recombinant cytokine stimulation, pharmacological NOX1 inhibition, in vitro growth and sphere formation assays, IL-17A KO mice with H. pylori/MNU-induced GC model Gastric cancer Medium 36125689
2023 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. Flow cytometry, qPCR, RNA-sequencing, immunoblotting, IL17RC-knockout cell line complementation with WT IL17RC Journal of clinical immunology High 38129603
2017 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. UVB irradiation of cultured fibroblasts, TGF-β1 treatment, Western blot, qPCR, ELISA, flow cytometry for receptor expression Frontiers in immunology Low 28217129
2026 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. Cell-type-specific IL-17RC knockout mice (intestinal epithelial and sympathetic neuron), microbiota analysis, chemical denervation, γδ T cell blockade, disease progression quantification bioRxivpreprint Medium 41959117

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. Journal of immunology (Baltimore, Md. : 1950) 283 17911633
2020 γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 151 32076265
2015 Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. The Journal of experimental medicine 151 25918342
2012 Hypomethylation of the IL17RC promoter associates with age-related macular degeneration. Cell reports 144 23177625
2010 IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 123 20231694
2008 IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood. Journal of immunology (Baltimore, Md. : 1950) 111 18097068
2010 IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail. Journal of immunology (Baltimore, Md. : 1950) 103 20554964
2009 IL-17RC: a partner in IL-17 signaling and beyond. Seminars in immunopathology 88 20012905
2010 IL-17A- versus IL-17F-induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in rheumatoid synoviocytes. Annals of the rheumatic diseases 69 21109515
2020 Structural Analysis Reveals that the Cytokine IL-17F Forms a Homodimeric Complex with Receptor IL-17RC to Drive IL-17RA-Independent Signaling. Immunity 65 32187518
2010 IL-17A suppresses the expression of bone resorption-related proteinases and osteoclast differentiation via IL-17RA or IL-17RC receptors in RAW264.7 cells. Biochimie 58 20045440
2007 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. Cytokine 54 17644350
2013 Hypomethylation of the IL17RC promoter in peripheral blood leukocytes is not a hallmark of age-related macular degeneration. Cell reports 42 24373284
2018 IL-17A, IL-17RC polymorphisms and IL17 plasma levels in Tunisian patients with rheumatoid arthritis. PloS one 33 29584788
2007 Differential expression of IL-17RC isoforms in androgen-dependent and androgen-independent prostate cancers. Neoplasia (New York, N.Y.) 28 17603628
2022 IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 27 36125689
2016 Neutrophils from F508del cystic fibrosis patients produce IL-17A and express IL-23 - dependent IL-17RC. Clinical immunology (Orlando, Fla.) 27 27155366
2012 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. BMC musculoskeletal disorders 25 22999050
2017 Increased IL-17RA and IL-17RC in End-Stage COPD and the Contribution to Mast Cell Secretion of FGF-2 and VEGF. Respiratory research 21 28298222
2019 Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid. Frontiers in immunology 19 31572359
2017 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. Frontiers in immunology 18 28217129
2016 Probable Chemical Hypoxia Effects on Progress of CNV Through Induction of Promoter CpG Demethylation and Overexpression of IL17RC in Human RPE Cells. Current eye research 17 26731132
2018 Association of IL17RC and COL6A1 genetic polymorphisms with susceptibility to ossification of the thoracic posterior longitudinal ligament in Chinese patients. Journal of orthopaedic surgery and research 15 29764467
2021 Self-assembled chitosan nanoparticles for intranasal delivery of recombinant protein interleukin-17 receptor C (IL-17RC): preparation and evaluation in asthma mice. Bioengineered 13 34180764
2017 Follistatin-like protein 1 modulates IL-17 signaling via IL-17RC regulation in stromal cells. Immunology and cell biology 12 28377613
2014 Overexpression of IL-17RC associated with ocular sarcoidosis. Journal of translational medicine 12 24885153
2021 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. Developmental and comparative immunology 10 34171369
2019 Potential role of the IL17RC gene in the thoracic ossification of the posterior longitudinal ligament. International journal of molecular medicine 10 30864693
2012 Association study of IL-17RC, CHL1, DSCAM and CNTNAP2 genes polymorphisms with adolescent idiopathic scoliosis susceptibility in a Chinese Han population. Studies in health technology and informatics 9 22744455
2017 IL-17RC is critically required to maintain baseline A20 production to repress JNK isoform-dependent tumor-specific proliferation. Oncotarget 8 28562353
2019 IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament. Journal of orthopaedic surgery and research 6 31291973
2023 Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC. Journal of clinical immunology 4 38129603
2025 Evolutionary insights and poly(I:C)-induced changes in expression and m6A modifications of il17ra and il17rc in Miichthysmiiuy. Fish & shellfish immunology 3 40239933
2025 The Association of IL-17RC Polymorphisms rs708567 and rs76999397 With Acute Lymphoblastic Leukaemia. International journal of immunogenetics 1 40887867
2023 Isolated chronic mucocutaneous candidiasis due to a novel duplication variant of IL17RC. Research square 1 37577484
2026 IL-17RC signaling connects intestinal microbiota and neuroimmune interactions in atherosclerosis. bioRxiv : the preprint server for biology 0 41959117
2025 Identification of an IL17RC missense variant in a Chinese family with multiple osteochondromas and ankylosing spondylitis. Journal of human genetics 0 40813448
2023 Oral candidiasis and seborrheic dermatitis in an 8-year-old female with a heterozygous variant of the IL-17RC gene. Pediatric dermatology 0 37254819

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