PLoS Pathogens | |
A Novel Inhibitory Mechanism of Mitochondrion-Dependent Apoptosis by a Herpesviral Protein | |
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
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO201902019219864ZK.pdf | 859KB | download |