Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response

Viral response The innate immune response, a vital defence against viral infections, is initiated when viral products induce type I interferon responses via the activation of Toll-like receptors and various cytoplasmic receptors. Two groups this week report on the properties of a molecule called TRAF3. Its function in immune cells was not previously known, but it is now shown to act as a convergence point for induction of the antiviral response by multiple viral recognition pathways. 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 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 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-ε, 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.