State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, China.
Mol Cell Biol. 2013 Aug;33(16):3137-49. doi: 10.1128/MCB.00030-13. Epub 2013 Jun 10.
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 型干扰素在宿主抗病毒感染中发挥重要作用。最近的报道表明，MAVS 对于病毒诱导的细胞凋亡也至关重要。然而，MAVS 介导的细胞凋亡诱导的机制尚不清楚。在这里，我们发现 MAVS 与电压依赖性阴离子通道 1（VDAC1）结合，并通过 caspase-3 激活诱导细胞凋亡，这与其在先天免疫中的作用无关。MAVS 通过降低其 K48 连接的泛素化降解来调节 VDAC1 蛋白稳定性。此外，MAVS 敲除的小鼠胚胎成纤维细胞（MEFs）显示 VDAC1 表达减少，导致水疱性口炎病毒（VSV）诱导的细胞凋亡反应减少。值得注意的是，在 MAVS 敲除 MEFs 中，VSV 感染引发的 VDAC1 上调完全被消除。因此，我们将 VDAC1 鉴定为 MAVS 的靶标，并描述了 MAVS 控制病毒诱导的细胞凋亡的新机制。
