GAMMAHV68 VMAP MITOCHONDRIAL ANTI-APOPTOSIS PROTEIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 一旦病毒感染，细胞就会发生凋亡，以防御病毒复制。反过来，病毒进化出了复杂的机制来颠覆细胞凋亡的过程。在这里，我们报道了一种新的小鼠伽马疱疹病毒68(GammaHV68)的病毒线粒体抗凋亡蛋白(VMAP)与Bcl2和VDAC1以基因和功能分离的方式相互作用。VMAP的N端两亲性α-螺旋区域与Bcl2相互作用，这种相互作用不仅显著增加了Bcl2对线粒体的募集，而且显著增加了其对BH3促凋亡蛋白的亲和力，从而抑制了Bax线粒体的移位和激活。此外，VMAP的中心疏水区和C末端疏水区与VDAC1相互作用，有效地抑制细胞色素c的释放。因此，这些相互作用导致对线粒体介导的细胞凋亡的全面抑制。最后，在正常细胞中，VMAP基因是有效的GammaHV68裂解复制所必需的，但在线粒体凋亡缺陷的细胞中不是。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Upon viral infection, cells undergo apoptosis as a defense against viral replication. Viruses, in turn, have evolved elaborate mechanisms to subvert apoptotic processes. Here, we report that a novel viral mitochondrial anti-apoptotic protein (vMAP) of murine gamma-herpesvirus 68 (gammaHV68) interacts with Bcl-2 and VDAC1 in a genetically and functionally separable manner. The N-terminal amphipathic alpha-helix region of vMAP interacted with Bcl-2 and this interaction markedly increased not only Bcl-2 recruitment to mitochondria but also its avidity for BH3-only proapoptotic proteins, thereby suppressing Bax mitochondrial translocation and activation. In addition, the central and C-terminal hydrophobic regions of vMAP interacted with VDAC1, resulting in effective inhibition of cytochrome c release. Consequently, these interactions induced the comprehensive inhibition of mitochondrion-mediated apoptosis. Finally, vMAP gene was required for efficient gammaHV68 lytic replication in normal cells, but not in mitochondrial apoptosis-deficient cells.