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

Nature. 2006 Jan 12;439(7073):208-11. doi: 10.1038/nature04374. Epub 2005 Nov 23.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • I-kappa B Kinase / metabolism
  • Immunity, Innate / immunology*
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology*
  • Interleukin-1 Receptor-Associated Kinases
  • Mice
  • Mice, Inbred C57BL
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • TNF Receptor-Associated Factor 3 / metabolism*
  • Toll-Like Receptor 3 / immunology
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism*
  • Virus Diseases / immunology*
  • Virus Diseases / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Irf3 protein, mouse
  • Irf7 protein, mouse
  • TICAM-1 protein, mouse
  • TNF Receptor-Associated Factor 3
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • Phosphotransferases (Alcohol Group Acceptor)
  • Tbk1 protein, mouse
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase