Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor.
Interleukin (IL)-17, the founding member of the IL-17 cytokine family, is the hallmark of a novel subset of CD4+ T cells that is regulated by TGFbeta, IL-6, and IL-23. IL-17 plays an important role in promoting tissue inflammation in host defense against infection and in autoimmune diseases. Although IL-17 has been reported to regulate the expression of proinflammatory cytokines, chemokines, and matrix metalloproteinases, the signaling mechanism of IL-17 receptor has not been understood. An earlier study found that IL-17 activates NF-kappaB and MAPK pathways and requires TRAF6 to induce IL-6. However, it is unknown what molecule(s) directly associates with IL-17 receptor to initiate the signaling. We demonstrate here that IL-17 receptor family shares sequence homology in their intracellular region with Toll-IL-1 receptor (TIR) domains and with Act1, a novel adaptor previously reported as an NF-kappaB activator. MyD88 and IRAK4, downstream signaling components of TIR, are not required for IL-17 signaling. On the other hand, Act1 and IL-17 receptor directly associate likely via homotypic interaction. Deficiency of Act1 in fibroblast abrogates IL-17-induced cytokine and chemokine expression, as well as the induction of C/EBPbeta, C/EBPdelta, and IkappaBzeta. Also, absence of Act1 results in a selective defect in IL-17-induced activation of NF-kappaB pathway. These results thus indicate Act1 as a membrane-proximal adaptor of IL-17 receptor with an essential role in induction of inflammatory genes. Our study not only for the first time reveals an immediate signaling mechanism downstream of an IL-17 family receptor but also has implications in therapeutic treatment of various immune diseases.
Chang
Seon Hee
SH
Department of Immunology, M D Anderson Cancer Center, Houston, Texas 77030, USA.
Park
Heon
H
Dong
Chen
C
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053722:Receptors, Interleukin-17 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D053722:Receptors, Interleukin-17; C515963:Traf3ip2 protein, mouse