The murine cytomegalovirus cell death suppressor m38.5 binds Bax and blocks Bax-mediated mitochondrial outer membrane permeabilization.
Apoptosis is increasingly implicated as an early line of defense against viral infections. Viruses have devised numerous strategies to delay apoptosis of infected cells. Many viruses encode cell death suppressors that target mitochondrial apoptotic signaling pathway, indicating the importance of this pathway in the anti-viral response. Human and primate cytomegaloviruses encode the viral mitochondria-localized inhibitor of apoptosis vMIA, but no overt homologue of vMIA was identified in any non-primate cytomegalovirus. Here we report that m38.5 protein encoded by murine cytomegalovirus, which is unrelated to vMIA in its amino acid sequence, delays death receptor ligation-induced cell death, and that m38.5 associates with Bax, recruits it to mitochondria, and blocks Bax-mediated but not Bak-mediated mitochondrial outer membrane permeabilization. Thus, primate and murine cytomegaloviruses have evolved non-homologous but functionally similar cell death suppressors selectively targeting the Bax-mediated branch of the mitochondrial apoptotic signaling pathway, indicating the importance of this branch in the response of diverse host organisms against cytomegalovirus infections.
Arnoult
Damien
D
INSERM U542, Hopital Paul Brousse, Université Paris-Sud, 14 Avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France. damien.arnoult@inserm.fr
Skaletskaya
Anna
A
Estaquier
Jérôme
J
Dufour
Cecilie
C
Goldmacher
Victor S
VS
D000818:Animals; D016923:Cell Death; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism*; D018146:Muromegalovirus / Q000378:metabolism*; D010539:Permeability; D011485:Protein Binding; D011487:Protein Conformation; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor