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

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.

• Authors: Ryoko Yoshida, Giichi Takaesu, Hideyuki Yoshida, Fuyuki Okamoto, Tomoko Yoshioka, Yongwon Choi, Shizuo Akira, Taro Kawai, Akihiko Yoshimura, Takashi Kobayashi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 52 Pg. 36211-20 (Dec 26 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18984593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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
• Receptors, Immunologic
• TNF Receptor-Associated Factor 6 (metabolism)