MAVS Regulates Apoptotic Cell Death by Decreasing K48-Linked Ubiquitination of Voltage-Dependent Anion Channel 1

The mitochondrial antiviral signaling protein MAVS (IPS-1, VISA, or Cardif) plays an important role in the host defense against viral infection by inducing type I interferon. Recent reports have shown that MAVS is also critical for virus-induced apoptosis. However, the mechanism of MAVS-mediated apoptosis induction remains unclear. Here, we show that MAVS binds to voltage-dependent anion channel 1 (VDAC1) and induces apoptosis by caspase-3 activation, which is independent of its role in innate immunity. MAVS modulates VDAC1 protein stability by decreasing its degradative K48-linked ubiquitination. In addition, MAVS knockout mouse embryonic fibroblasts (MEFs) display reduced VDAC1 expression with a consequent reduction of the vesicular stomatitis virus (VSV)-induced apoptosis response. Notably, the upregulation of VDAC1 triggered by VSV infection is completely abolished in MAVS knockout MEFs. We thus identify VDAC1 as a target of MAVS and describe a novel mechanism of MAVS control of virus-induced apoptotic cell death.

线粒体抗病毒信号蛋白MAVS（IPS - 1、VISA或Cardif）通过诱导I型干扰素在宿主抵御病毒感染中发挥重要作用。近期报道表明，MAVS对病毒诱导的细胞凋亡也至关重要。然而，MAVS介导细胞凋亡诱导的机制仍不清楚。在此，我们发现MAVS与电压依赖性阴离子通道1（VDAC1）结合，并通过激活半胱天冬酶 - 3诱导细胞凋亡，这与其在先天免疫中的作用无关。MAVS通过降低VDAC1的降解性K48连接的泛素化来调节VDAC1蛋白的稳定性。此外，MAVS基因敲除的小鼠胚胎成纤维细胞（MEFs）显示VDAC1表达降低，从而导致水疱性口炎病毒（VSV）诱导的细胞凋亡反应减弱。值得注意的是，在MAVS基因敲除的MEFs中，VSV感染引发的VDAC1上调完全被消除。因此，我们确定VDAC1是MAVS的一个靶点，并描述了一种MAVS控制病毒诱导的凋亡细胞死亡的新机制。