Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.
Type I interferon (IFN) production is a critical component of the innate defence against viral infections. Viral products induce strong type I IFN responses through the activation of Toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as protein kinase R (PKR). Here we demonstrate that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs. Furthermore, we show that TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation. In addition to TLR stimulation, we also show that TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways. Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response.
Oganesyan
Gagik
G
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 609 Charles E. Young Dr. East, Los Angeles, California 90095, USA.
Saha
Supriya K
SK
Guo
Beichu
B
He
Jeannie Q
JQ
Shahangian
Arash
A
Zarnegar
Brian
B
Perry
Andrea
A
Cheng
Genhong
G
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014777:Virus Diseases / Q000276:immunology* / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D053592:Interleukin-1 Receptor-Associated Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C476286:Ticam1 protein, mouse; C498588:Tbk1 protein, mouse; C507769:Irak1 protein, mouse