IL17RC

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).

1. 2007 High

   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

   PMID:17911633

   Open questions at the time

   • 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
2. 2008 Medium

   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

   PMID:18097068

   Open questions at the time

   • Mechanism of receptor cooperation was not defined
   • Physical association of the two receptors was not tested
3. 2010 High

   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

   PMID:20231694 PMID:20554964

   Open questions at the time

   • 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
4. 2015 High

   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

   PMID:25918342

   Open questions at the time

   • 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
5. 2017 Medium

   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

   PMID:28377613 PMID:28562353

   Open questions at the time

   • 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
6. 2020 High

   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

   PMID:32187518

   Open questions at the time

   • 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
7. 2020 High

   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

   PMID:32076265

   Open questions at the time

   • 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
8. 2023 Medium

   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

   PMID:38129603

   Open questions at the time

   • Genotype–phenotype correlation across partial vs complete IL-17RC deficiency is still limited to few families
   • Broader immune phenotyping beyond CMC not performed

• 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.
• 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