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 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.
Maitra
Amarnath
A
Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
Shen
Fang
F
Hanel
Walter
W
Mossman
Karen
K
Tocker
Joel
J
Swart
David
D
Gaffen
Sarah L
SL
D020816:Amino Acid Motifs; D000601:Amino Acids, Essential / Q000737:chemistry; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053722:Receptors, Interleukin-17 / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D000601:Amino Acids, Essential; D022782:CCAAT-Enhancer-Binding Protein-beta; D053722:Receptors, Interleukin-17