Zan Jie, Liu Juan, Zhou Jian-Wei, Wang Hai-Long, Mo Kai-Kun, Yan Yan, Xu Yun-Bin, Liao Min, Su Shuo, Hu Rong-Liang, Zhou Ji-Yong
Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou, PR China.
Institute of Immunology, Nanjing Agricultural University, Nanjing, PR China.
Exp Cell Res. 2016 Sep 10;347(1):83-94. doi: 10.1016/j.yexcr.2016.07.008. Epub 2016 Jul 15.
Apoptosis, as an innate antiviral defense, not only functions to limit viral replication by eliminating infected cells, but also contribute to viral dissemination, particularly at the late stages of infection. A highly neurotropic CVS strain of rabies virus induces apoptosis both in vitro and in vivo. However, the detailed mechanism of CVS-mediated neuronal apoptosis is not entirely clear. Here, we show that CVS induces apoptosis through mitochondrial pathway by dissipating mitochondrial membrane potential, release of cytochrome c and AIF. CVS blocks Bax activation at the early stages of infection; while M protein partially targets mitochondria and induces mitochondrial apoptosis at the late stages of infection. The α-helix structure spanning 67-79 amino acids of M protein is essential for mitochondrial targeting and induction of apoptosis. These results suggest that CVS functions on mitochondria to regulate apoptosis at different stages of infection, so as to for viral replication and dissemination.
细胞凋亡作为一种先天性抗病毒防御机制，不仅通过清除受感染细胞来限制病毒复制，还会促进病毒传播，尤其是在感染后期。狂犬病病毒的一种高度嗜神经性CVS毒株在体外和体内均可诱导细胞凋亡。然而，CVS介导的神经元凋亡的详细机制尚不完全清楚。在此，我们表明CVS通过耗散线粒体膜电位、释放细胞色素c和凋亡诱导因子，通过线粒体途径诱导细胞凋亡。CVS在感染早期阻断Bax激活；而M蛋白在感染后期部分靶向线粒体并诱导线粒体凋亡。M蛋白67-79个氨基酸的α-螺旋结构对于线粒体靶向和凋亡诱导至关重要。这些结果表明，CVS作用于线粒体以调节感染不同阶段的细胞凋亡，从而促进病毒复制和传播。
