Antiapoptotic activity of the herpesvirus saimiri-encoded Bcl-2 homolog: stabilization of mitochondria and inhibition of caspase-3-like activity.
Viruses have evolved different strategies to interfere with host cell apoptosis. Herpesvirus saimiri (HVS) and other lymphotropic herpesviruses code for proteins that are homologous to the cellular antiapoptotic Bcl-2. In this study HVS-Bcl-2 was stably expressed in the human leukemia cell line Jurkat and in the murine T-cell hybridoma DO to assess its antiapoptotic spectrum and to gain further insight into its mode of action. HVS- Bcl-2 prevented apoptosis that occurs as a result of a disturbance of intracellular homeostasis by, for example, DNA damage or menadione, which gives rise to oxygen radicals. In Jurkat cells, HVS-Bcl-2 also inhibited apoptosis mediated by the death receptor CD95. In DO cells, HVS-Bcl-2 did not interfere with CD95-mediated apoptosis but blocked dexamethasone-induced cell death. Mitochondrial damage is a central coordinating event in apoptosis induced by different stimuli. To assess the integrity of mitochondria, we used rhodamine 123, which is released upon disturbance of the mitochondrial membrane potential, and determined the release of cytochrome c into the cytosol. Both signs of mitochondrial damage were prevented by HVS-Bcl-2. This viral protein also inhibited the generation of caspase-3-like DEVDase activity and blocked the cleavage of poly(ADP-ribose) polymerase, a natural substrate of caspase-3-like proteases. In conclusion, HVS-Bcl-2 protects against a great variety of apoptotic stimuli, stabilizes mitochondria, and acts upstream of the generation of caspase-3-like activity.
Derfuss
T
T
Institut für Klinische und Molekulare Virologie, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Fickenscher
H
H
Kraft
M S
MS
Henning
G
G
Lengenfelder
D
D
Fleckenstein
B
B
Meinl
E
E
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005609:Free Radicals; D006567:Herpesvirus 2, Saimiriine / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D010718:Phosphatidylserines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014162:Transfection; D014764:Viral Proteins / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology
D005609:Free Radicals; D010718:Phosphatidylserines; D019253:Proto-Oncogene Proteins c-bcl-2; D015842:Serine Proteinase Inhibitors; D014764:Viral Proteins; D019014:fas Receptor; D003907:Dexamethasone; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases