期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 276, 期 2, 页码 1185-1194出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M006647200
关键词
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资金
- NCI NIH HHS [R01 CA074892] Funding Source: Medline
Double-stranded RNA (dsRNA) molecules generated during virus infection can initiate a host antiviral response to limit further infection. Such a response involves induction of antiviral gene expression by the dsRNA-activated protein kinase (PKR) and the NF-kappaB transcription factor. In addition, dsRNA can also induce apoptosis by an incompletely understood mechanism that may servo to further limit viral replication. Here we demonstrate a novel role for the RelA subunit of NF-KB in inhibiting dsRNA-induced cell death, dsRNA treatment resulted in caspase 3 activation and apoptotic morphological transformations in mouse embryonic fibroblasts (MEFs) derived from RelA-/- mice but not from RelA+/- mice. Such dsRNA-induced killing could be inhibited by expression of either a dominant-negative mutant of PKR or wild-type RelA Interestingly, caspase 3 activated following dsRNA treatment of RelA-/- MEFs was essential for apoptotic nuclear changes but dispensable for cytotoxicity. A broader specificity caspase inhibitor was also unable to inhibit dsRNA-induced cytotoxicity, suggesting that caspase activation is not essential for the induction of cell death by dsRNA in MEFs. However, combined inhibition of caspase 3 and reactive oxygen species production resulted in complete inhibition of dsRNA-induced cytotoxicity. These results demonstrate an essential role for NF-kappaB in protecting cells from dsRNA-induced apoptosis and suggest that NF-kappaB may inhibit both caspase-dependent and reactive oxygen species-dependent cytotoxic pathways.
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