| First Author | Maitra A | Year | 2007 |
| Journal | Proc Natl Acad Sci U S A | Volume | 104 |
| Issue | 18 | Pages | 7506-11 |
| PubMed ID | 17456598 | Mgi Jnum | J:121350 |
| Mgi Id | MGI:3709827 | Doi | 10.1073/pnas.0611589104 |
| Citation | Maitra A, et al. (2007) Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc Natl Acad Sci U S A 104(18):7506-11 |
| abstractText | 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 TNFalpha and IL-1beta, 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-kappaB, MAPK, and up-regulation of C/EBPbeta and C/EBPdelta. Mutagenesis of the TILL domain revealed a site analogous to the LPS(d) mutation in TLR4, which renders mice insensitive to LPS. 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/EBPbeta 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. |
