Williamson Chad D, Colberg-Poley Anamaris M
Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010, USA.
Rev Med Virol. 2009 May;19(3):147-64. doi: 10.1002/rmv.611.
By exploiting host cell machineries, viruses provide powerful tools for gaining insight into cellular pathways. Proteins from two unrelated viruses, human CMV (HCMV) and HCV, are documented to traffic sequentially from the ER into mitochondria, probably through the mitochondria-associated membrane (MAM) compartment. The MAM are sites of ER-mitochondrial contact enabling the direct transfer of membrane bound lipids and the generation of high calcium (Ca2+) microdomains for mitochondria signalling and responses to cellular stress. Both HCV core protein and HCMV UL37 proteins are associated with Ca2+ regulation and apoptotic signals. Trafficking of viral proteins to the MAM may allow viruses to manipulate a variety of fundamental cellular processes, which converge at the MAM, including Ca2+ signalling, lipid synthesis and transfer, bioenergetics, metabolic flow, and apoptosis. Because of their distinct topologies and targeted MAM sub-domains, mitochondrial trafficking (albeit it through the MAM) of the HCMV and HCV proteins predictably involves alternative pathways and, hence, distinct targeting signals. Indeed, we found that multiple cellular and viral proteins, which target the MAM, showed no apparent consensus primary targeting sequences. Nonetheless, these viral proteins provide us with valuable tools to access the poorly characterised MAM compartment, to define its cellular constituents and describe how virus infection alters these to its own end. Furthermore, because proper trafficking of viral proteins is necessary for their function, discovering the requirements for MAM to mitochondrial trafficking of essential viral proteins may provide novel targets for the rational design of anti-viral drugs.
通过利用宿主细胞机制，病毒为深入了解细胞通路提供了强大工具。来自两种不相关病毒——人类巨细胞病毒（HCMV）和丙型肝炎病毒（HCV）的蛋白质被证明依次从内质网进入线粒体，可能是通过线粒体相关膜（MAM）区室。MAM是内质网与线粒体接触的位点，能够直接转移膜结合脂质，并产生高钙（Ca2+）微区，用于线粒体信号传导和对细胞应激的反应。HCV核心蛋白和HCMV UL37蛋白都与Ca2+调节和凋亡信号相关。病毒蛋白向MAM的转运可能使病毒能够操纵多种在MAM处汇聚的基本细胞过程，包括Ca2+信号传导、脂质合成与转移、生物能量学、代谢流和凋亡。由于HCMV和HCV蛋白具有不同的拓扑结构和靶向的MAM亚结构域，它们向线粒体的转运（尽管是通过MAM）可预测地涉及不同的途径，因此具有不同的靶向信号。事实上，我们发现多种靶向MAM的细胞和病毒蛋白没有明显一致的主要靶向序列。尽管如此，这些病毒蛋白为我们提供了宝贵的工具，用于进入特征不明的MAM区室，确定其细胞成分，并描述病毒感染如何将这些成分改变以满足自身目的。此外，由于病毒蛋白的正确转运对其功能至关重要，发现必需病毒蛋白从MAM到线粒体转运的要求可能为合理设计抗病毒药物提供新的靶点。
