TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway

Ryoko Yoshida, Giichi Takaesu, Hideyuki Yoshida, Fuyuki Okamoto, Tomoko Yoshioka, Yongwon Choi, Shizuo Akira, Taro Kawai, Akihiko Yoshimura, Takashi Kobayashi

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70 Citations (Scopus)

Abstract

Type I interferons (IFN-α/β) are essential for immune defense against viruses and induced through the actions of the cytoplasmic helicases, RIG-I and MDA5, and their downstream adaptor molecule IPS-1. TRAF6 and the downstream kinase TAK1 have been shown to be essential for the production of proinflammatory cytokines through the TLR/MyD88/TRIF pathway. Although binding of TRAF6 with IPS-1 has been demonstrated, the role of the TRAF6 pathway in IFN-α/β production has not been fully understood. Here, we demonstrate that TRAF6 is critical for IFN-α/β induction in response to viral infection and intracellular double-stranded RNA, poly(I:C). Activation of NF-κB, JNK, and p38, but not IRF3, was impaired in TRAF6-deficient mouse embryo fibroblasts in response to vesicular stomatitis virus and poly(I:C). However, TAK1 was not required for IFN-β induction in this process, since normal IFN-α/β production was observed in TAK1-deficient mouse embryo fibroblasts. Instead, another MAP3K, MEKK1, was important for the activation of the IFN-β promoter in response to poly(I:C). Forced expression of MEKK1 in combination with IRF3 was sufficient for the induction of IFN-β, whereas suppression of MEKK1 expression by small interfering RNA inhibited the induction of IFN-β by poly(I:C). These data suggest that IPS-1 requires TRAF6 and MEKK1 to activate NF-κB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons.

Original languageEnglish
Pages (from-to)36211-36220
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number52
DOIs
Publication statusPublished - 2008 Dec 26

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yoshida, R., Takaesu, G., Yoshida, H., Okamoto, F., Yoshioka, T., Choi, Y., Akira, S., Kawai, T., Yoshimura, A., & Kobayashi, T. (2008). TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. Journal of Biological Chemistry, 283(52), 36211-36220. https://doi.org/10.1074/jbc.M806576200