Bcl-2 and Bcl-xL overexpression inhibits cytochrome c release, activation of multiple caspases, and virus release following coxsackievirus B3 infection.
Coxsackievirus B3, a cytopathic virus in the family Picornaviridae, induces degenerative changes in host cell morphology. Here we demonstrate cytochrome c release and caspases-2, -3, -6, -7, -8, and -9 processing. Enforced Bcl-2 and Bcl-xL expression markedly reduced release of cytochrome c, presentation of the mitochondrial epitope 7A6, and depressed caspase activation following infection. In comparison, cell death using TRAIL ligand caused caspase-8 processing prior to cytochrome c release and executioner caspases and cell death was only partially rescued by Bcl-2 and Bcl-xL overexpression. Disruption of the mitochondrial inner membrane potential following CVB3 infection was not inhibited by zVAD.fmk treatment. Bcl-2 or Bcl-xL overexpression or zVAD.fmk treatment delayed the loss of host cell viability and decreased progeny virus release following infection. Our data suggest that mitochondrial release of cytochrome c may be an important early event in caspase activation in CVB3 infection, and, as such, may contribute to the loss of host-cell viability and progeny virus release.
Carthy
Christopher M
CM
Department of Pathology and Laboratory Medicine, University of British Columbia-St. Paul's Hospital, The iCAPTUR4E Centre/McDonald Research Laboratories, 1081 Burrard Street, Vancouver, British Columbia, Canada V6Z 1Y6.
Yanagawa
Bobby
B
Luo
Honglin
H
Granville
David J
DJ
Yang
Decheng
D
Cheung
Paul
P
Cheung
Caroline
C
Esfandiarei
Mitra
M
Rudin
Charles M
CM
Thompson
Craig B
CB
Hunt
David W C
DW
McManus
Bruce M
BM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003384:Coxsackievirus Infections / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000502:physiology*; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D061945:Caspase Inhibitors; D000939:Epitopes; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D045304:Cytochromes c; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases