MAVS-MKK7-JNK2 defines a novel apoptotic signaling pathway during viral infection.
MAVS-MKK7-JNK2 defines a novel apoptotic signaling pathway during viral infection.
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DOI：
10.1371/journal.ppat.1004020
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Huang Y;Liu H;Li S;Tang Y;Wei B;Yu H;Wang C
病毒感染诱导先天免疫和细胞凋亡。细胞凋亡是杀死病毒感染的宿主细胞，从而限制病原体传播的有效手段。然而，这一过程的基本机制仍然知之甚少。在这里，我们表明，线粒体抗病毒信号蛋白（MAVS/VISA/Cardif/IPS-1）是SeV（仙台病毒）诱导的细胞凋亡的关键。MAVS特异性激活c-Jun N-末端激酶2（JNK 2），但不激活其他MAP激酶。Jnk 2 −/−细胞，而不是Jnk 1 −/−细胞，不能启动病毒诱导的凋亡，SeV进一步未能触发MAPK激酶7（MKK 7）敲除（Mkk 7 −/−）细胞的凋亡。从机制上讲，MAVS通过其3D结构域将MKK 7募集到线粒体上，随后磷酸化JNK 2，从而激活凋亡途径。一致的是，在病毒攻击后，Jnk 2 −/−小鼠而不是Jnk 1 −/−小鼠在肺和肝中显示出显著的炎性损伤。总的来说，我们已经确定了一种新的信号通路，涉及MAVS-MKK 7-JNK 2，它介导病毒诱导的细胞凋亡，并强调了线粒体外膜在宿主防御中不可或缺的作用。线粒体抗病毒信号蛋白（MAVS/VISA/Cardif/IPS-1）对于病毒感染期间的先天免疫应答是关键的，并且其功能在介导I型干扰素产生中已被充分证明。在这项研究中，我们揭示了MAVS在病毒诱导的细胞凋亡中的重要作用，独立于视黄酸诱导基因I（RIG-I）信号传导。在病毒感染后，MAVS将MKK 7募集到线粒体上，随后MKK 7诱导JNK 2的活化，其随后启动细胞凋亡。重要的是，我们已经清楚地区分了JNK 2与JNK 1，MKK 7与MKK 4在病毒诱导的细胞凋亡中的作用。因此，我们定义了一种新的凋亡信号通路，涉及MAVS-MKK 7-JNK 2，这为先天免疫中抗病毒和凋亡信号通路之间的串扰提供了新的视角。
Viral infection induces innate immunity and apoptosis. Apoptosis is an effective means to sacrifice virus-infected host cells and therefore restrict the spread of pathogens. However, the underlying mechanisms of this process are still poorly understood. Here, we show that the mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for SeV (Sendai virus)-induced apoptosis. MAVS specifically activates c-Jun N-terminal kinase 2 (JNK2) but not other MAP kinases. Jnk2−/− cells, but not Jnk1−/− cells, are unable to initiate virus-induced apoptosis and SeV further fails to trigger apoptosis in MAPK kinase 7 (MKK7) knockout (Mkk7−/−) cells. Mechanistically, MAVS recruits MKK7 onto mitochondria via its 3D domain, which subsequently phosphorylates JNK2 and thus activates the apoptosis pathway. Consistently, Jnk2−/− mice, but not Jnk1−/− mice, display marked inflammatory injury in lung and liver after viral challenge. Collectively, we have identified a novel signaling pathway, involving MAVS-MKK7-JNK2, which mediates virus-induced apoptosis and highlights the indispensable role of mitochondrial outer membrane in host defenses. The mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for the innate immune response during viral infection, and its function has been well documented in mediating type I interferon production. In this study, we revealed the essential role of MAVS in virus-induced apoptosis, independent of Retinoic acid-Inducible Gene I (RIG-I) signaling. Upon viral infection, MAVS recruits MKK7 onto mitochondria, followed by MKK7 induced activation of JNK2, which subsequently initiates apoptosis. Importantly, we have clearly differentiated the roles of JNK2 versus JNK1, and MKK7 versus MKK4 in virus-induced apoptosis. Thus, we define a novel apoptotic signaling pathway, involving MAVS-MKK7-JNK2, which sheds a new perspective on the crosstalk between the antiviral and apoptotic signaling pathways in innate immunity.
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