Feng, PinghuiLiang, ChengyuShin, Young CheolE, XiaofeiZhang, WeijunGravel, RobynWu, Ting-tingSun, RenUsherwood, EdwardJung, Jae Ung2011-12-212007Feng, Pinghui, Chengyu Liang, Young C. Shin, Xiaofei E., Weijun Zhang, Robyn Gravel, Ting-ting Wu, Ren Sun, Edward Usherwood, and Jae U. Jung. 2007. A novel inhibitory mechanism of mitochondrion-dependent apoptosis by a herpesviral protein. PLoS Pathogens 3(12): e174.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:5691130Upon 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 γ-herpesvirus 68 (γHV-68) interacts with Bcl-2 and voltage-dependent anion channel 1 (VDAC1) in a genetically separable manner. The N-terminal 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 pro-apoptotic proteins, thereby suppressing Bax mitochondrial translocation and activation. In addition, the central and C-terminal hydrophobic regions of vMAP interacted with VDAC1. Consequently, these interactions resulted in the effective inhibition of cytochrome c release, leading to the comprehensive inhibition of mitochondrion-mediated apoptosis. Finally, vMAP gene was required for efficient γHV-68 lytic replication in normal cells, but not in mitochondrial apoptosis-deficient cells. These results demonstrate that γHV-68 vMAP independently targets two important regulators of mitochondrial apoptosis-mediated intracellular innate immunity, allowing efficient viral lytic replication.en-USJournal Article2011-12-2110.1371/journal.ppat.0030174