Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.
Oganesyan, Gagik 1,2*; Saha, Supriya K. 1,2*; Guo, Beichu 1; He, Jeannie Q. 1; Shahangian, Arash 1,2; Zarnegar, Brian 1; Perry, Andrea 1; Cheng, Genhong 1,3
[Letter] Nature. 439(7073):208-211, January 12, 2006.

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Type I interferon (IFN) production is a critical component of the innate defence against viral infections 1. 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) 2-12. 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-[small element of], 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.

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