TRAF6 and MEKK1 Play a Pivotal Role in the RIG-I-like Helicase Antiviral Pathway
TRAF6 and MEKK1 Play a Pivotal Role in the RIG-I-like Helicase Antiviral Pathway
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DOI：
10.1074/jbc.m806576200
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发表时间：
2008-12-26
影响因子：
4.8
通讯作者：
Kobayashi, Takashi
中科院分区：
文献类型：
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作者：
Yoshida, Ryoko;Takaesu, Giichi;Kobayashi, Takashi
I型干扰素（IFN-α/β）对于针对病毒的免疫防御是必需的，并且通过细胞质解旋酶RIG-I和MDA 5及其下游衔接分子IPS-1的作用诱导。TRAF 6和下游激酶TAK 1已被证明是通过TLR/MyD 88/TRIF途径产生促炎细胞因子所必需的。虽然已经证明TRAF 6与IPS-1的结合，但TRAF 6途径在IFN α/β产生中的作用尚未完全了解。在这里，我们证明TRAF 6是关键的IFN-α/β诱导响应病毒感染和细胞内的双链RNA，聚（I：C）。在TRAF 6缺陷小鼠胚胎成纤维细胞中，NF-κ B、JNK和p38的激活在水泡性口炎病毒和poly（I：C）的反应中受损，但IRF 3未受损。然而，在这个过程中，TAK 1不是IFN-β诱导所必需的，因为在TAK 1缺陷的小鼠胚胎成纤维细胞中观察到正常的IFN-α/β产生。相反，另一种MAP 3 K，MEKK 1，对于响应poly（I：C）的IFN-β启动子的激活是重要的。MEKK 1与IRF 3组合的强制表达足以诱导IFN-β，而通过小干扰RNA抑制MEKK 1表达抑制了poly（I：C）对IFN-β的诱导。这些数据表明，IPS-1需要TRAF 6和MEKK 1来激活NF-κ B和丝裂原活化蛋白激酶，这些蛋白激酶对于I型干扰素的最佳诱导是至关重要的。
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.