Decreased Intracellular Superoxide Levels Activate Sindbis Virus-induced Apoptosis

Infection of many cultured cell types with Sindbis virus (SV), an alphavirus, triggers apoptosis through a commonly utilized caspase activation pathway. However, the upstream signals by which SV activates downstream apoptotic effectors, including caspases, remain unclear. Here we report that in AT-3...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-05, Vol.274 (19), p.13650-13655
Main Authors: Lin, Kuo-I, Pasinelli, Piera, Brown, Robert H., Hardwick, J. Marie, Ratan, Rajiv R.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Apoptosis - physiology
Hydrogen Peroxide - metabolism
Male
Mice
Paraquat - pharmacology
Prostatic Neoplasms - enzymology
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Sindbis virus
Sindbis Virus - drug effects
Sindbis Virus - physiology
Superoxide Dismutase - metabolism
Superoxides - metabolism
Tumor Cells, Cultured
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Summary:Infection of many cultured cell types with Sindbis virus (SV), an alphavirus, triggers apoptosis through a commonly utilized caspase activation pathway. However, the upstream signals by which SV activates downstream apoptotic effectors, including caspases, remain unclear. Here we report that in AT-3 prostate carcinoma cells, SV infection decreases superoxide (O⨪2) levels within minutes of infection as monitored by an aconitase activity assay. This SV-induced decrease in O⨪2 levels appears to activate or modulate cell death, as a recombinant SV expressing the O⨪2 scavenging enzyme, copper/zinc superoxide dismutase (SOD), potentiates SV-induced apoptosis. A recombinant SV expressing a mutant form of SOD, which has reduced SOD activity, has no effect. The potentiation of SV-induced apoptosis by wild type SOD is because of its ability to scavenge intracellular O⨪2 rather than its ability to promote the generation of hydrogen peroxide. Pyruvate, a peroxide scavenger, does not affect the ability of wild type SOD to potentiate cell death; and increasing the intracellular catalase activity via a recombinant SV vector has no effect on SV-induced apoptosis. Moreover, increasing intracellular O⨪2 by treatment of 3T3 cells with paraquat protects them from SV-induced death. Altogether, our results suggest that SV may activate apoptosis by reducing intracellular superoxide levels and define a novel redox signaling pathway by which viruses can trigger cell death.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.19.13650