期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 52, 页码 36211-36220出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806576200
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- National Institute of Biomedical Innovation (NIBIO)
- Nakatomi Foundation
- Takeda Science Foundation
- Kato Memorial Trust Foundation for Nanbyo Research
- Suzuken Memorial Foundation
- Japan Intractable Disease Research Foundation
- Naito Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Astellas Foundation for Research on Metabolic Disorders
- Yakult Bioscience Research Foundation
- Princess Takamatsu Cancer Research
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-kappa B, 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-kappa B and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons.
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