IL-17 Receptor Family Review

The IL-17 receptor family now consists of 5 members, IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE, all of which, like their ligands, share sequence homology. Each of these members is a subunit that needs to associate with another one to form the functional receptor. The subunit IL-17RA is ubiquitous, and is encoded by a gene situated on chromosome 22, while others are encoded by a cluster on chromosome 3. It is also a common co-receptor subunit for other members of the IL-17 family.

Below will briefly discuss each IL-17 receptor family member and their functions, including IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE.

IL-17 receptor family and IL-17 family

IL-17 Receptor Family: IL-17RA

IL-17 receptor A (IL-17RA) was identified as a new cytokine receptor for IL-17A in 1995 and was later found to be part of a cytokine receptor family unrelated to existing cytokine receptor family.

Different from other IL-17 receptors, IL-17RA contains two extra domains, a TILL [TIR (Toll/IL-1R)-like loop] domain close behind the SEFIR domain and a Distal domain in the C-terminus. IL-17RA appears to be a common subunit in the IL-17 receptor family to form heterodimeric complexes with other IL-17 receptors.

The mechanism of IL-17 cytokine and receptor complex formation was shown to be unique and involved the engagement of IL-17 by two fibronectin-type domains of IL-17RA. Binding of the first receptor to IL-17 modulated the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric compared with homodimeric complex formation.

IL-17RA is expressed ubiquitously, with particularly high levels in haemopoietic tissues. however, the main responsive cells to IL-17 are epithelial cells, endothelial cells and fibroblasts, although macrophages and DCs are also responsive.

IL-17 Receptor Family: IL-17RB

IL-17RB is expressed by various endocrine tissues as well as the kidneys, liver and Th2 cells. IL-17RB binds both IL-17B and IL-17E.

Unlike IL-17RA, other members of the IL-17 receptor family are highly spliced at sites in the extracellular domain, potentially giving rise to both agonistic and antagonistic (soluble) forms of the receptors, although it hasn't been reported about the role of each splice variant of IL-17RB.

IL-17 Receptor Family: IL-17RC

IL-17RC was identified by homology searches of mammalian expressed sequence tag (EST) databases. IL-17RC contains a SEFIR domain but not an obvious TILL domain. IL-17RC is required for IL-17A and IL-17F mediated signaling, but it cannot induce signaling in the absence of IL-17RA. The IL-17RC cytoplasmic tail is required for signal transduction but not for inducible co‑immunoprecipitation with IL-17RA.

Similarly to IL-17RB, IL-17RC is highly spliced in the extracellular domain. More than 90 splice isoforms of IL-17RC were identified in human prostate cancer lines, but only 4 splice variants of mouse IL-17RC are found in EST databases. There is ligand preference of IL-17RC splice isoforms, as certain forms bind preferentially to IL-17A or IL-17F. Furthermore, some isoforms do not bind either cytokine, suggesting that there might be additional ligands for this receptor subunit.
of CLF-1/p28 binding to a trimeric receptor complex composed of IL-27RA/gp130/IL-6RA.

IL-17 Receptor Family: IL-17RD

IL-17RD was first identified in zebrafish on the basis of a similar expression pattern to the fibroblast growth factor receptor (FGFR) and thus is commonly known as SEF (similar expression to the FGFR). IL-17RD has no known ligand.
IL-17RD seems to be the most evolutionarily ancient member of the IL-17 receptor family, as it has homologues in sea lamprey, frogs and C. elegans.

IL-17RD inhibits FGF-mediated Ras-MAPK and PI3K signalling during both zebrafish and frog development. IL-17RD blocks FGF in part by physically associating with FGFR1 and FGFR2. The cytoplasmic tail of IL-17RD is required for its ability to inhibit signaling and associate with FGFR, but the extracellular domain is dispensable. The human homologue of IL-17RD also co-immunoprecipitates with FGFR1 and can inhibit FGF‑dependent ERK activation and FGF-dependent proliferation.

IL-17RD can also interact with IL-17RA, although the biological importance of this association remains unclear36. IL-17RD deficient mice are viable and have no obvious developmental abnormalities, but detailed phenotypic analysis has not yet been carried out.

IL-17 Receptor Family: IL-17RE

IL-17RE is the least well understood member of the IL-17 receptor family, but recent studies suggest that its ligand is IL-17C. IL-17RE is highly spliced, with six isoforms identified in EST databases. Ectopic expression of an EPOR–IL-17RE construct in the myeloid BaF3 cell line indicated that this receptor might promote proliferation, but this occurred in a ligand-independent manner, which raises concerns about the validity of the assay system.

References

1. Gu, C., Wu, L., & Li, X. (2013). IL-17 family: cytokines, receptors and signaling. Cytokine, 64(2), 477-485.
2. Gaffen, S. L. (2009). Structure and signalling in the IL-17 receptor family. Nature Reviews Immunology, 9(8), 556-567.