Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide.
Sindbis virus (SV) causes acute encephalomyelitis by infecting and inducing the death of neurons. Induction of apoptosis occurs during virus entry and involves acid-induced conformational changes in the viral surface glycoproteins and sphingomyelin (SM)-dependent fusion of the virus envelope with the endosomal membrane. We have studied neuroblastoma cells to determine how this entry process triggers cell death. Acidic sphingomyelinase was activated during entry followed by activation of neutral sphingomyelinase, SM degradation, and a sustained increase in ceramide. Ceramide-induced apoptosis and SV-induced apoptosis could be inhibited by treatment with Z-VAD-fmk, a caspase inhibitor, and by overexpression of Bcl-2, an antiapoptotic cellular protein. Acid ceramidase, expressed in a recombinant SV, decreased intracellular ceramide and protected cells from apoptosis. The data suggest that acid-induced SM-dependent virus fusion initiates the apoptotic cascade by inducing SM degradation and ceramide release.
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W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Chatterjee
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Griffin
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D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002517:Galactosylgalactosylglucosylceramidase / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D012845:Sindbis Virus / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D002518:Ceramides; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D010749:Phosphoprotein Phosphatases; D013108:Sphingomyelin Phosphodiesterase; D002517:Galactosylgalactosylglucosylceramidase; D020169:Caspases