Structure and signalling in the IL-17 receptor family

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Abstract
The cytokine IL-17A came into the limelight with the discovery of T helper 17 (TH17) cells, a new CD4+ T cell subset that represents the first main revision of the TH1–TH2 cell paradigm in 2 decades. IL-17A and its receptor are founding members of a new family of cytokines (IL-17A–IL-17F) and cytokine receptors (IL-17RA–IL-17RE) that have unique structures and signalling properties. Although they are produced by different cell types, all IL-17 family cytokines seem to promote inflammation, both in host defence and in inflammatory pathology. IL-17RA, a receptor for IL-17A and IL-17F, is the founding member of the IL-17R family and seems to function as a co-receptor with at least two other members of the IL-17R family. IL-17RA is expressed ubiquitously as a pre-associated multimeric receptor, but is also dynamically regulated in certain cell types. IL-17RA has the largest cytoplasmic tail of the family, which potentially provides docking sites for numerous signalling intermediates. Acting through a SEF/IL-17R (SEFIR) domain, which is conserved between but also unique to the IL-17R family, IL-17RA engages the ACT1 adaptor to induce the nuclear factor-κB, mitogen-activated protein kinase and CCAAT/enhancer-binding protein signalling pathways. IL-17RC is a co-receptor with IL-17RA that triggers IL-17A- and IL-17F-mediated signalling, and IL-17RB associates with IL-17RA to mediate IL-17E-induced signalling. Far less is known about how these other receptors activate downstream signalling pathways. Efforts to target IL-17 family cytokines, particularly IL-17A and IL-17RA, are underway for the treatment of autoimmune diseases. Understanding the molecular features of this cytokine family will provide useful information for therapeutic uses.