title: 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.affiliation: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yoshida
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Okamoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D016207:Cytokines; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016898:Interferon-alpha; D016899:Interferon-beta; D048728:MAP Kinase Kinase Kinase 1; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C482576:MAP3K1 protein, human; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse