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

J Biol Chem. 2008 Dec 26;283(52):36211-20. doi: 10.1074/jbc.M806576200. Epub 2008 Nov 4.

Abstract

Type I interferons (IFN-alpha/beta) 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-alpha/beta production has not been fully understood. Here, we demonstrate that TRAF6 is critical for IFN-alpha/beta induction in response to viral infection and intracellular double-stranded RNA, poly(I:C). Activation of NF-kappaB, 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-beta induction in this process, since normal IFN-alpha/beta production was observed in TAK1-deficient mouse embryo fibroblasts. Instead, another MAP3K, MEKK1, was important for the activation of the IFN-beta promoter in response to poly(I:C). Forced expression of MEKK1 in combination with IRF3 was sufficient for the induction of IFN-beta, whereas suppression of MEKK1 expression by small interfering RNA inhibited the induction of IFN-beta by poly(I:C). These data suggest that IPS-1 requires TRAF6 and MEKK1 to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antiviral Agents / pharmacology*
  • Cytokines / metabolism
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism*
  • Fibroblasts / metabolism
  • Humans
  • Interferon-alpha / metabolism
  • Interferon-beta / metabolism
  • MAP Kinase Kinase Kinase 1 / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • TNF Receptor-Associated Factor 6 / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • Cytokines
  • IPS-1 protein, mouse
  • Interferon-alpha
  • TNF Receptor-Associated Factor 6
  • VISA protein, human
  • Interferon-beta
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • DDX58 protein, human
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases