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


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.


  1. Isaacs, A. & Lindenmann, J. Virus interference. I. The interferon. By A. Isaacs and J. Lindenmann, 1957. J. Interferon Res. 7, 429–438 (1987)

    CAS  Article  Google Scholar 

  2. Balachandran, S. et al. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13, 129–141 (2000)

    CAS  Article  Google Scholar 

  3. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001)

    CAS  Article  ADS  Google Scholar 

  4. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)

    CAS  Article  ADS  Google Scholar 

  5. Heil, F. et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303, 1526–1529 (2004)

    CAS  Article  ADS  Google Scholar 

  6. Hemmi, H., Kaisho, T., Takeda, K. & Akira, S. The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. 170, 3059–3064 (2003)

    CAS  Article  Google Scholar 

  7. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol. 3, 196–200 (2002)

    CAS  Article  Google Scholar 

  8. Hochrein, H. et al. Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 101, 11416–11421 (2004)

    CAS  Article  ADS  Google Scholar 

  9. Krug, A. et al. Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103, 1433–1437 (2004)

    CAS  Article  Google Scholar 

  10. Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598–5603 (2004)

    CAS  Article  ADS  Google Scholar 

  11. Doyle, S. et al. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17, 251–263 (2002)

    CAS  Article  Google Scholar 

  12. Tabeta, K. et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl Acad. Sci. USA 101, 3516–3521 (2004)

    CAS  Article  ADS  Google Scholar 

  13. Dempsey, P. W., Doyle, S. E., He, J. Q. & Cheng, G. The signaling adaptors and pathways activated by TNF superfamily. Cytokine Growth Factor Rev. 14, 193–209 (2003)

    CAS  Article  Google Scholar 

  14. Cao, Z., Xiong, J., Takeuchi, M., Kurama, T. & Goeddel, D. V. TRAF6 is a signal transducer for interleukin-1. Nature 383, 443–446 (1996)

    CAS  Article  ADS  Google Scholar 

  15. Xu, Y., Cheng, G. & Baltimore, D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 5, 407–415 (1996)

    CAS  Article  Google Scholar 

  16. Fitzgerald, K. A. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunol. 4, 491–496 (2003)

    CAS  Article  Google Scholar 

  17. Cheng, G. & Baltimore, D. TANK, a co-inducer with TRAF2 of TNF- and CD 40L-mediated NF-κB activation. Genes Dev. 10, 963–973 (1996)

    CAS  Article  Google Scholar 

  18. Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003)

    CAS  Article  ADS  Google Scholar 

  19. Pomerantz, J. L. & Baltimore, D. NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 18, 6694–6704 (1999)

    CAS  Article  Google Scholar 

  20. Sasai, M. et al. Cutting edge: NF-κB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation. J. Immunol. 174, 27–30 (2005)

    CAS  Article  Google Scholar 

  21. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)

    CAS  Article  ADS  Google Scholar 

  22. Kawai, T. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nature Immunol. 5, 1061–1068 (2004)

    CAS  Article  Google Scholar 

  23. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003)

    CAS  Article  ADS  Google Scholar 

  24. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003)

    CAS  Article  ADS  Google Scholar 

  25. Siegal, F. P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999)

    CAS  Article  Google Scholar 

  26. Uematsu, S. et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction. J. Exp. Med. 201, 915–923 (2005)

    CAS  Article  Google Scholar 

  27. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004)

    CAS  Article  Google Scholar 

  28. Chu, W. M. et al. JNK2 and IKKβ are required for activating the innate response to viral infection. Immunity 11, 721–731 (1999)

    CAS  Article  Google Scholar 

  29. Gil, J. et al. TRAF family proteins link PKR with NF-κB activation. Mol. Cell. Biol. 24, 4502–4512 (2004)

    CAS  Article  Google Scholar 

  30. Perry, A. K., Chow, E. K., Goodnough, J. B., Yeh, W. C. & Cheng, G. Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. J. Exp. Med. 199, 1651–1658 (2004)

    CAS  Article  Google Scholar 

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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).

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