Inhibition of Programmed Cell Death by Cytomegalovirus

程序性细胞死亡（PCD）作为一种天然免疫防御病毒感染的重要机制。在以前的工作中，我们已经表明，鼠巨细胞病毒（MCMV）编码至少四个细胞死亡抑制剂：M36蛋白抑制死亡受体介导的凋亡，通过阻断caspase-8激活。最近，我们已经表明MCMV M45蛋白结合细胞衔接蛋白RIP 1并阻断RIP 1介导的PCD以及NF-κ B和p38 MAP激酶的激活。M45作为RIP 1介导的信号传导（vIRS）的抑制剂的功能代表了病毒干扰细胞应激反应的新机制。最近发表的数据表明，MCMV编码几个线粒体蛋白，这些蛋白可能在线粒体检查点参与PCD的抑制。我们已经证明MCMV m38.5蛋白特异性阻断BAX介导的细胞死亡，并且我们实验室的初步数据表明病毒小线粒体蛋白（vSMP）负责抑制巴克。在拟议的项目中，我们希望分析病毒蛋白vIRS和vSMP的功能特性，以及这些蛋白在人巨细胞病毒中可能的同源物。

Programmed cell death (PCD) plays an important role as an innate immune defense against viral infections. In previous work we have shown that murine cytomegalovirus (MCMV) encodes at least four cell death inhibitors: The M36 protein inhibits death receptor-mediated apoptosis by blocking caspase-8 activation. More recently, we have shown that the MCMV M45 protein binds to the cellular adapter protein RIP1 and blocks RIPl-meditated PCD and the activation of NF-KB and p38 MAP kinase. M45 s function as an inhibitor of RIP1- mediated signalling (vIRS) represents a novel mechanism of viral interference with the cellular stress response. Recently published data suggest that MCMV encodes several mitochondrial proteins, which could participate in the inhibition of PCD at the mitochondrial checkpoint. We have shown that the MCMV m38.5 protein specifically blocks BAX-mediated cell death, and preliminary data from our laboratory indicate that a viral small mitochondrial protein (vSMP) is responsible for inhibiting BAK. In the proposed project we want to analyze the functional properties of the viral proteins vIRS and vSMP as well as possible homologs of these proteins in human cytomegalovirus.