期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 18, 页码 7506-7511出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0611589104
关键词
BB-loop; cytokine; inflammation; Toll/IL-1R domain; CCAAT/enhancer binding protein
资金
- NIAID NIH HHS [AI43929, R15 AI043929] Funding Source: Medline
- NIAMS NIH HHS [R21 AR050458, AR050458] Funding Source: Medline
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 undescribedTIR-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.
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