The IRF-3 Transcription Factor Mediates Sendai Virus-Induced Apoptosis

doi:10.1128/JVI.74.8.3781-3792.2000

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Journal of Virology, April 2000, p. 3781-3792, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The IRF-3 Transcription Factor Mediates Sendai Virus-Induced Apoptosis

Christophe Heylbroeck,¹^,² Siddharth Balachandran,³ Marc J. Servant,¹^,⁴ Carmela DeLuca,¹^,⁴ Glen N. Barber,³ Rongtuan Lin,¹^,²^,³ and John Hiscott¹^,²^,³^,^*

Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital,¹ and Departments of Microbiology and Immunology² and Medicine,⁴ McGill University, Montreal, Quebec, Canada H3T 1E2, and Sylvester Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Miami, Miami, Florida 33136³

Received 8 October 1999/Accepted 21 January 2000

Virus infection of target cells can result in different biological outcomes: lytic infection, cellular transformation, orcell death by apoptosis. Cells respond to virus infection by theactivation of specific transcription factors involved in cytokinegene regulation and cell growth control. The ubiquitously expressedinterferon regulatory factor 3 (IRF-3) transcription factor isdirectly activated following virus infection through posttranslationalmodification. Phosphorylation of specific C-terminal serine residuesresults in IRF-3 dimerization, nuclear translocation, and activationof DNA-binding and transactivation potential. Once activated,IRF-3 transcriptionally up regulates alpha/beta interferon genes,the chemokine RANTES, and potentially other genes that inhibitviral infection. We previously generated constitutively active[IRF-3(5D)] and dominant negative (IRF-3 $Delta$ N) forms of IRF-3 thatcontrol target gene expression. In an effort to characterize thegrowth regulatory properties of IRF-3, we observed that IRF-3is a mediator of paramyxovirus-induced apoptosis. Expression ofthe constitutively active form of IRF-3 is toxic, preventing theestablishment of stably transfected cells. By using a tetracycline-induciblesystem, we show that induction of IRF-3(5D) alone is sufficientto induce apoptosis in human embryonic kidney 293 and human JurkatT cells as measured by DNA laddering, terminal deoxynucleotidyltransferase-mediateddUTP-biotin nick end labeling assay, and analysis of DNA contentby flow cytometry. Wild-type IRF-3 expression augments paramyxovirus-inducedapoptosis, while expression of IRF-3 $Delta$ N blocks virus-induced apoptosis.In addition, we demonstrate an important role of caspases 8, 9,and 3 in IRF-3-induced apoptosis. These results suggest that IRF-3,in addition to potently activating cytokine genes, regulates apoptoticsignalling following virusinfection.

^* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal, Quebec,Canada H3T1E2. Phone: (514) 340-8222, ext. 5265. Fax: (514) 340-7576.E-mail: mijh{at}musica.mcgill.ca.

Journal of Virology, April 2000, p. 3781-3792, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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