The IRF-3 transcription factor mediates sendai virus-induced apoptosis

Virus infection of target cells can result in different biological outcomes : lytic infection, cellular transformation, or cell death by apoptosis, Cel ls respond to virus infection by the activation of specific transcription f actors involved in cytokine gene regulation and cell growth control, The ub iquitously expressed interferon regulatory factor. 3 (IRF-3) transcription factor is directly activated following virus infection through posttranslat ional modification. Phosphorylation of specific C-terminal serine residues results in IRF-3 dimerization, nuclear translocation, and activation of DNA -binding and transactivation potential. Once activated, IRF-3 transcription ally up regulates alpha/beta interferon genes, the chemokine RANTES, and po tentially other genes that inhibit viral infection. We previously generated constitutively active [IRF-3(5D)] and dominant negative (IRF-3 Delta N) fo rms of IRF-3 that control target gene expression. In an effort to character ize the grow-th regulatory properties of IRF-3, we observed that IRF-3 is a mediator of paramyxovirus-induced apoptosis, Expression of the constitutiv ely active form of IRF-3 is toxic, preventing the establishment of stably t ransfected cells, By using a tetracycline-inducible system, we show that in duction of IRF-3(5D) alone is sufficient to induce apoptosis in human embry onic kidney 293 and human Jurkat T cells as measured by DNA laddering, term inal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling ass ay, and analysis of DNA content by flow cytometry, Wild-type IRF-3 expressi on augments paramyxovirus-induced apoptosis, while expression of IRF-3 Delt a N blocks virus-induced apoptosis, In addition, we demonstrate an importan t role of caspases 8, 9, and 3 in IRF-3-induced apoptosis, These results su ggest that IRF-3, in addition to potently activating cytokine genes, regula tes apoptotic signalling following virus infection.