Signaling motifs in the IL-17 receptor (94.2)

Abstract IL-17 and its receptor IL-17RA have received much attention as the defining cytokine of a new class of T helper cells termed Th17. Mounting evidence suggests that IL-17 causes pathology in autoimmunity, but surprisingly little is known about mechanisms of IL-17 signal transduction. Although produced by T cells, IL-17 activates genes typical of innate immune cytokines such as TNFα and IL-1β, despite little sequence similarity in their respective receptors. A prior bioinformatics study predicted a subdomain in IL-17-family receptors with homology to a Toll/IL-1R (TIR) domain, termed “SEFIR.” However, the SEFIR domain lacks motifs critical for bona fide TIR domains, and its functionality has never been verified. Here, we used a reconstitution system in IL-17RA-null fibroblasts to map functional domains within IL-17RA. We demonstrate for the first time that the SEFIR domain mediates signaling, independently of TIR adaptors such as MyD88 and TRIF. Moreover, we identified a novel “TIR-like loop” (TILL) also required for activation of NF-κB, NF-κB-dependent genes and upregulation of C/EBPβ and C/EBPδ. We further identified a distinct domain required for activation of C/EBPβ and induction of a subset IL-17 target genes. This is the first structure-function analysis of any IL-17R superfamily receptor, and reveals unique structural and functional properties in IL-17 signaling.