title: Vaccinia virus infection disarms the mitochondrion-mediated pathway of the apoptotic cascade by modulating the permeability transition pore.
abstract: Many viruses have evolved strategies that target crucial components within the apoptotic cascade. One of the best studied is the caspase 8 inhibitor, crmA/Spi-2, encoded by members of the poxvirus family. Since many proapoptotic stimuli induce apoptosis through a mitochondrion-dependent, caspase 8-independent pathway, we hypothesized that vaccinia virus would encode a mechanism to directly modulate the mitochondrial apoptotic pathway. In support of this, we observed that Jurkat cells, which undergo Fas-mediated apoptosis exclusively through the mitochondrial route, were resistant to Fas-induced death following infection with a crmA/Spi-2-deficient strain of vaccinia virus. In addition, vaccinia virus-infected cells subjected to the proapoptotic stimulus staurosporine exhibited decreased levels of both cytochrome c released from the mitochondria and caspase 3 activation. In all cases we found that the loss of the mitochondrial membrane potential, which occurs as a result of opening the multimeric permeability transition pore complex, was prevented in vaccinia virus-infected cells. Moreover, vaccinia virus infection specifically inhibited opening of the permeability transition pore following treatment with the permeability transition pore ligand atractyloside and t-butylhydroperoxide. These studies indicate that vaccinia virus infection directly impacts the mitochondrial apoptotic cascade by influencing the permeability transition pore.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
authors.forename: S T
authors.initials: ST
authors.lastname: Wasilenko
authors.forename: A F
authors.initials: AF
authors.lastname: Meyers
authors.forename: K
authors.initials: K
authors.lastname: Vander Helm
authors.forename: M
authors.initials: M
authors.lastname: Barry
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D006868:Hydrolysis; D019169:Jurkat Cells; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D014616:Vaccinia virus / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D017931:DNA Primers; D019014:fas Receptor; D019311:Staurosporine