Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression

IL-17 is the founding member of a novel family of proinflammatory cytokines that defines a new class of CD4(+) effector T cells, termed "Th17." Mounting evidence suggests that IL-17 and Th17 cells cause pathology in autoimmunity, but little is known about mechanisms of IL-17RA signaling. IL-17 through its receptor (IL-17RA) activates genes typical of innate immune cytokines, such as TNF alpha and IL-1 beta, despite minimal sequence similarity in their respective receptors. A previous bioinformatics study predicted a subdomain in IL-17-family receptors with homology to a Toll/IL-1R (TIR) domain, termed the "SEFIR domain." However, the SEFIR domain lacks motifs critical for bona fide TIR domains, and its functionality was never verified. Here, we used a reconstitution system in IL-17RA-null fibroblasts to map functional domains within IL-17RA. We demonstrate that the SEFIR domain mediates IL-17RA signaling independently of classic TIR adaptors, such as MyD88 and TRIF. Moreover, we identified a previously undescribed"TIR-like loop" (TILL) required for activation of NF-kappa B, MAPK, and up-regulation of C/EBP beta and C/EBP delta. Mutagenesis of the TILL domain revealed a site analogous to the LpS(d) mutation in TLR4, which renders mice insensitive to LIPS. However, a putative salt bridge typically found in TIR domains appears to be dispensable. We further identified a C-terminal domain required for activation of C/EBP beta and induction of a subset IL-17 target genes. This structure-function analysis of a IL-17 superfamily receptor reveals important differences in IL-17RA compared with IL-1/TLR receptors.