A Novel Inhibitory Mechanism of Mitochondrion-Dependent Apoptosis by a Herpesviral Protein

PLoS Pathogens

Robyn Gravel¹  Jae U Jung¹  Ting-ting Wu²  Pinghui Feng²  Weijun Zhang²  Xiaofei E²  Young C Shin²  Chengyu Liang³  Ren Sun⁴  Edward Usherwood⁴ 

[1] Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire, United States of America;Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, United States of America;Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America;Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, California, United States of America

关键词: Mitochondria;    Apoptosis;    Immunoprecipitation;    Immunoblotting;    Viral replication;    Protein interactions;    293T cells;    Glutathione chromatography;   

DOI  :  10.1371/journal.ppat.0030174

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 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.

【 授权许可】

CC BY