A novel inhibitory mechanism of mitochondrion-dependent apoptosis by a herpesviral protein

PLoS Pathog. 2007 Dec;3(12):e174. doi: 10.1371/journal.ppat.0030174.

Abstract

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 (gammaHV-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 gammaHV-68 lytic replication in normal cells, but not in mitochondrial apoptosis-deficient cells. These results demonstrate that gammaHV-68 vMAP independently targets two important regulators of mitochondrial apoptosis-mediated intracellular innate immunity, allowing efficient viral lytic replication.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Base Sequence
  • Cell Line
  • Chlorocebus aethiops
  • Gammaherpesvirinae / genetics
  • Gammaherpesvirinae / metabolism*
  • Gene Expression Regulation, Viral
  • Host-Pathogen Interactions
  • Humans
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Molecular Sequence Data
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Two-Hybrid System Techniques
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Replication
  • Voltage-Dependent Anion Channel 1 / genetics
  • Voltage-Dependent Anion Channel 1 / metabolism*
  • Yeasts / genetics
  • Yeasts / metabolism

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Viral Proteins
  • Voltage-Dependent Anion Channel 1

Associated data

  • GENBANK/BC053380
  • GENBANK/L37296
  • GENBANK/U16811
  • GENBANK/U75506
  • GENBANK/U97553
  • RefSeq/NM_000633
  • RefSeq/NM_138578