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Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6

Nature Immunology volume 5, pages 1061–1068 (2004)Cite this article

Abstract

Toll-like receptors (TLRs) are involved in the recognition of microbial pathogens. A subset of TLRs, TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-α (IFN-α). Production of IFN-α is dependent on the Toll–interleukin-1 receptor domain–containing adaptor MyD88. Here we show that MyD88 formed a complex with the transcription factor IRF7 but not with IRF3. The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-α-dependent promoters. Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation. These results indicate that TLR-mediated IFN-α induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination.

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Figure 1: MyD88 associates with IRF7.
Figure 2: Colocalization of MyD88 and IRF7 demonstrated by FRET analysis.
Figure 3: IRF7 activation by MyD88.
Figure 4: MyD88-dependent activation of IRF7 by TLR9 ligand.
Figure 5: IRF7 activation by TRAF6.
Figure 6: Ubiquitin E3 ligase activity of TRAF6 is required for IRF7 activation.

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Acknowledgements

We thank K. Irie, A. Yamaguchi and A. Shibano for technical support; M. Hashimoto for secretarial assistance; S. Tanaka (Nippon Becton Dickinson Company) for FRET analysis; and F. Takeshita (Department of Molecular Biodefense Research, School of Medicine, Yokohama City University) for discussions and support.

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Authors and Affiliations

  1. ERATO, Akira Innate Immunity Program, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Taro Kawai, Shintaro Sato, Ken J Ishii, Cevayir Coban, Osamu Takeuchi & Shizuo Akira

  2. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Hiroaki Hemmi, Masahiro Yamamoto, Satoshi Uematsu, Osamu Takeuchi & Shizuo Akira

  3. Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Kenta Terai & Michiyuki Matsuda

  4. Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Jun-ichiro Inoue

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Correspondence to Shizuo Akira.

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Kawai, T., Sato, S., Ishii, K. et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5, 1061–1068 (2004). https://doi.org/10.1038/ni1118

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