Apoptosis is promoted by the dsRNA-activated factor (DRAF1) during viral infection independent of the action of interferon or p53.
An apoptotic cellular defense mechanism is triggered in response to viral dsRNA generated during the course of infection by many DNA and RNA viruses. We demonstrate that apoptosis induced by dsRNA or a paramyxovirus is independent of the action of interferon as it can proceed in a variety of cell lines and primary cells deficient in an interferon response. Initiation of apoptosis appears to be triggered by activation of a cellular transcription factor, the dsRNA-activated factor (DRAF1). DRAF1 is composed of interferon regulatory factor 3 (IRF-3) and the transcriptional coactivators CREB binding protein (CBP) or p300. We find that activation of IRF-3 in the absence of viral infection stimulates apoptosis. In addition, a negative interfering mutant blocks both target gene induction and apoptosis, demonstrating a requirement for gene expression by IRF-3/DRAF1 to promote apoptosis. IRF-3/DRAF1 target gene expression is also induced in response to a distinct apoptotic stimulus, the DNA damaging agent etoposide. The activity of the p53 tumor suppressor does not appear to be required for IRF-3/DRAF1-mediated apoptosis.
Weaver
B K
BK
Department of Pathology, State University of New York at Stony Brook, New York 11794, USA.
Ando
O
O
Kumar
K P
KP
Reich
N C
NC
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D050882:CREB-Binding Protein; D002467:Cell Nucleus / Q000648:ultrastructure; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000633:toxicity; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007372:Interferons / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009522:Newcastle disease virus / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D004268:DNA-Binding Proteins; C110908:DRAF1 transcription factor; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; D005047:Etoposide; D007372:Interferons; D050882:CREB-Binding Protein; C494363:CREBBP protein, human