GAMMAHV68 VMAP MITOCHONDRIAL ANTI-APOPTOSIS PROTEIN

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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.