Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy

Abstract

IL-17 is the defining cytokine of a newly-described "Th17" population that plays critical roles in mediating inflammation and autoimmunity. The IL-17/IL-17 receptor superfamily is the most recent class of cytokines and receptors to be described, and until recently very little was known about its function or molecular biology. However, in the last year important new insights into the composition and dynamics of the receptor complex and mechanisms of downstream signal transduction have been made, which will be reviewed here.

Figure 1. Cytokine receptor superfamilies

The five major subgroups of cytokine receptors are depicted, including the Type I hematopoietin receptors, Type II interferon receptors, TNF receptors, IL-1/Toll-like receptors and the IL-17 receptor family. Major conserved sequence elements are included. Box1 and Box2 are JAK-binding domains. “TIR” is the Toll-like receptor/IL-1 receptor interacting domain, and SEFIR is the SEF/IL-17 receptor domain. See Section 1 in the text for details.

Figure 2. Homotypic interactions between IL-17RA subunits

The IL-17RA is predicted to contain two fibronectin III-like (FN) motifs connected by an unstructured linker, and interacts via the FN2 motif in a ligand-independent manner as shown by fluorescence resonance energy transfer (FRET) studies. CFP, cyan fluorescent protein. YFP, yellow fluorescent protein. See section 3–section 4 in the text for details.

Figure 3. Signal tranduction by the IL-17 receptor complex

The IL-17R is composed of at least two IL-17RA subunit and at least one IL-17RC subunit, although the precise stoichiometry is still undefined. Binding of ligand [IL-17(A), IL-17F or IL-17A/F] triggers signaling mediated through at least two motifs in the IL-17RA tail: a SEFIR/TILL domain, which contains elements homologous to TIR domains, and a distal domain that activates C/EBPβ. The major signaling intermediates so far identified include Act1, TAK1 and TRAF6, which coordinate NF-κB and probably MAPK and C/EBP activation. Activation of these pathways leads to gene expression mediated the levels of transcription and mRNA stability. JAK1 and PI3K pathways have also been implicated, but far less is known about whether and how this occurs. See Section 5 in the text for details.