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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, or cell death by
apoptosis. Cells respond to virus infection by the activation of
specific transcription factors involved in cytokine gene regulation and
cell growth control. The ubiquitously expressed interferon regulatory
factor 3 (IRF-3) transcription factor is directly activated following
virus infection through posttranslational 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 transcriptionally up
regulates alpha/beta interferon genes, the chemokine RANTES, and
potentially other genes that inhibit viral infection. We previously
generated constitutively active [IRF-3(5D)] and dominant negative
(IRF-3
N) forms of IRF-3 that control target gene expression. In an
effort to characterize the growth regulatory properties of IRF-3, we
observed that IRF-3 is a mediator of paramyxovirus-induced apoptosis.
Expression of the constitutively active form of IRF-3 is toxic,
preventing the establishment of stably transfected cells. By using a
tetracycline-inducible system, we show that induction of IRF-3(5D)
alone is sufficient to induce apoptosis in human embryonic kidney 293 and human Jurkat T cells as measured by DNA laddering, terminal
deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling
assay, and analysis of DNA content by flow cytometry. Wild-type IRF-3
expression augments paramyxovirus-induced apoptosis, while expression
of IRF-3
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 apoptotic signalling following
virus infection.
*
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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