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

Abstract

Type I interferon (IFN) production is a critical component of the innate defence against viral infections1. 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.

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Figure 1: Induction of the type I IFN response by TLR3 and TLR4 requires TRAF3.
Figure 2: TRAF3 associates with IFN pathway mediators and is required for TLR3-induced IRF3 activation.
Figure 3: TRAF3 is required for TLR7/9-dependent type I IFN production.
Figure 4: Involvement of TRAF3 in TLR-independent antiviral responses.

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Acknowledgements

G.O., S.K.S. and A.S. are supported by a UCLA Medical Scientist Training Program training grant. B.G. is supported by the Tumour Immunology Fellowship. B.Z. is supported by the Warsaw Fellowship. A.P. is supported by a H.H.M.I. pre-doctoral fellowship. G.C. is a Lymphoma and Leukemia Society Scholar, and part of this work was also supported by National Institutes of Health research grants.

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Correspondence to Genhong Cheng.

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Oganesyan, G., Saha, S., Guo, B. et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439, 208–211 (2006). https://doi.org/10.1038/nature04374

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