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

Gagik Oganesyan; Supriya K Saha; Beichu Guo; Jeannie Q He; Arash Shahangian; Brian Zarnegar; Andrea Perry; Genhong Cheng

doi:10.1038/nature04374

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.

Authors

Gagik Oganesyan¹, Supriya K Saha, Beichu Guo, Jeannie Q He, Arash Shahangian, Brian Zarnegar, Andrea Perry, Genhong Cheng

Affiliation

¹ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 609 Charles E. Young Dr. East, Los Angeles, California 90095, USA.

PMID: 16306936
DOI: 10.1038/nature04374

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