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 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.
Lin
K I
KI
Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pasinelli
P
P
Brown
R H
RH
Hardwick
J M
JM
Ratan
R R
RR
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D010269:Paraquat / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D012845:Sindbis Virus / Q000187:drug effects / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D013481:Superoxides; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D010269:Paraquat