TRAF6 establishes innate immune responses by activating NF-κB and IRF7 upon sensing cytosolic viral RNA and DNA

Hiroyasu Konno, Takuya Yamamoto, Kohsuke Yamazaki, Jin Gohda, Taishin Akiyama, Kentaro Senba, Hideo Goto, Atsushi Kato, Toshiaki Yujiri, Takahiko Imai, Yasushi Kawaguchi, Bing Su, Osamu Takeuchi, Shizuo Akira, Yasuko Tsunetsugu-Yokota, Jun Ichiro Inoue

    Research output: Contribution to journalArticle

    61 Citations (Scopus)

    Abstract

    Background: In response to viral infection, the innate immune system recognizes viral nucleic acids and then induces production of proinflammatory cytokines and type I interferons (IFNs). Toll-like receptor 7 (TLR7) and TLR9 detect viral RNA and DNA, respectively, in endosomal compartments, leading to the activation of nuclear factor κB (NF-κB) and IFN regulatory factors (IRFs) in plasmacytoid dendritic cells. During such TLR signaling, TNF receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB and the production of type I IFN. In contrast, RIG-like helicases (RLHs), cytosolic RNA sensors, are indispensable for antiviral responses in conventional dendritic cells, macrophages, and fibroblasts. However, the contribution of TRAF6 to the detection of cytosolic viral nucleic acids has been controversial, and the involvement of TRAF6 in IRF activation has not been adequately addressed. Principal Findings: Here we first show that TRAF6 plays a critical role in RLH signaling. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of IL-6 and type I IFNs after infection with RNA virus. Activation of NF-κB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFβ-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-κB activation, were not essential for RLH-mediated NF-κB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA induced antiviral responses, and this impairment was due to defective activation of NF-κB and IRF7. Conclusions/Significance: Thus, TRAF6 mediates antiviral responses triggered by cytosolic viral DNA and RNA in a way that differs from that associated with TLR signaling. Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection.

    Original languageEnglish
    Article numbere5674
    JournalPLoS One
    Volume4
    Issue number5
    DOIs
    Publication statusPublished - 2009 May 25

    Fingerprint

    TNF Receptor-Associated Factor 6
    Viral DNA
    Viral RNA
    Innate Immunity
    RNA
    receptors
    Chemical activation
    DNA
    Interferon Type I
    interferons
    Antiviral Agents
    Immune system
    Virus Diseases
    dendritic cells
    Dendritic Cells
    Nucleic Acids
    Immune System
    nucleic acids
    RNA Virus Infections
    Toll-Like Receptor 7

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    TRAF6 establishes innate immune responses by activating NF-κB and IRF7 upon sensing cytosolic viral RNA and DNA. / Konno, Hiroyasu; Yamamoto, Takuya; Yamazaki, Kohsuke; Gohda, Jin; Akiyama, Taishin; Senba, Kentaro; Goto, Hideo; Kato, Atsushi; Yujiri, Toshiaki; Imai, Takahiko; Kawaguchi, Yasushi; Su, Bing; Takeuchi, Osamu; Akira, Shizuo; Tsunetsugu-Yokota, Yasuko; Inoue, Jun Ichiro.

    In: PLoS One, Vol. 4, No. 5, e5674, 25.05.2009.

    Research output: Contribution to journalArticle

    Konno, H, Yamamoto, T, Yamazaki, K, Gohda, J, Akiyama, T, Senba, K, Goto, H, Kato, A, Yujiri, T, Imai, T, Kawaguchi, Y, Su, B, Takeuchi, O, Akira, S, Tsunetsugu-Yokota, Y & Inoue, JI 2009, 'TRAF6 establishes innate immune responses by activating NF-κB and IRF7 upon sensing cytosolic viral RNA and DNA', PLoS One, vol. 4, no. 5, e5674. https://doi.org/10.1371/journal.pone.0005674
    Konno, Hiroyasu ; Yamamoto, Takuya ; Yamazaki, Kohsuke ; Gohda, Jin ; Akiyama, Taishin ; Senba, Kentaro ; Goto, Hideo ; Kato, Atsushi ; Yujiri, Toshiaki ; Imai, Takahiko ; Kawaguchi, Yasushi ; Su, Bing ; Takeuchi, Osamu ; Akira, Shizuo ; Tsunetsugu-Yokota, Yasuko ; Inoue, Jun Ichiro. / TRAF6 establishes innate immune responses by activating NF-κB and IRF7 upon sensing cytosolic viral RNA and DNA. In: PLoS One. 2009 ; Vol. 4, No. 5.
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    AU - Konno, Hiroyasu

    AU - Yamamoto, Takuya

    AU - Yamazaki, Kohsuke

    AU - Gohda, Jin

    AU - Akiyama, Taishin

    AU - Senba, Kentaro

    AU - Goto, Hideo

    AU - Kato, Atsushi

    AU - Yujiri, Toshiaki

    AU - Imai, Takahiko

    AU - Kawaguchi, Yasushi

    AU - Su, Bing

    AU - Takeuchi, Osamu

    AU - Akira, Shizuo

    AU - Tsunetsugu-Yokota, Yasuko

    AU - Inoue, Jun Ichiro

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    N2 - Background: In response to viral infection, the innate immune system recognizes viral nucleic acids and then induces production of proinflammatory cytokines and type I interferons (IFNs). Toll-like receptor 7 (TLR7) and TLR9 detect viral RNA and DNA, respectively, in endosomal compartments, leading to the activation of nuclear factor κB (NF-κB) and IFN regulatory factors (IRFs) in plasmacytoid dendritic cells. During such TLR signaling, TNF receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB and the production of type I IFN. In contrast, RIG-like helicases (RLHs), cytosolic RNA sensors, are indispensable for antiviral responses in conventional dendritic cells, macrophages, and fibroblasts. However, the contribution of TRAF6 to the detection of cytosolic viral nucleic acids has been controversial, and the involvement of TRAF6 in IRF activation has not been adequately addressed. Principal Findings: Here we first show that TRAF6 plays a critical role in RLH signaling. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of IL-6 and type I IFNs after infection with RNA virus. Activation of NF-κB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFβ-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-κB activation, were not essential for RLH-mediated NF-κB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA induced antiviral responses, and this impairment was due to defective activation of NF-κB and IRF7. Conclusions/Significance: Thus, TRAF6 mediates antiviral responses triggered by cytosolic viral DNA and RNA in a way that differs from that associated with TLR signaling. Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection.

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