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J. Biol. Chem., Vol. 282, Issue 30, 21953-21961, July 27, 2007

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Retinoic Acid-inducible Gene-I and Interferon- Promoter Stimulator-1 Augment Proapoptotic Responses Following Mammalian Reovirus Infection via Interferon Regulatory Factor-3^*

Geoffrey H. Holm, Jennifer Zurney^¶1, Vanessa Tumilasci^||12, Simon Leveille^||, Pranav Danthi, John Hiscott^||3, Barbara Sherry^¶**, and Terence S. Dermody⁴

From the Departments of Pediatrics and Microbiology and Immunology and the Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, the Departments of ^¶Microbiology and ^**Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina 27606, and the ^||Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec H3T 1E2, Canada

During viral infection, cells initiate antiviral responses to contain replication and inhibit virus spread. One protective mechanism involves activation of transcription factors interferon regulatory factor-3 (IRF-3) and NF-B, resulting in secretion of the antiviral cytokine, interferon-. Another is induction of apoptosis, killing the host cell before virus disseminates. Mammalian reovirus induces both interferon- and apoptosis, raising the possibility that both pathways are initiated by a common cellular sensor. We show here that reovirus activates IRF-3 with kinetics that parallel the activation of NF-B, a known mediator of reovirus-induced apoptosis. Activation of IRF-3 requires functional retinoic acid inducible gene-I and interferon- promoter stimulator-1, but these intracellular sensors are dispensable for activation of NF-B. Interferon- promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response.

Received for publication, March 12, 2007 , and in revised form, May 8, 2007.

^* This work was supported by Public Health Service Awards T32 AI49824 and F32 AI071440 (to G. H. H.), R01 AI50080 (to T. S. D.), and R01 AI62657 (to B. S.), by the Elizabeth B. Lamb Center for Pediatric Research, and by grants from the Canadian Institutes of Health Research, the National Cancer Institute of Canada, the Canadian Cancer Society, and the Terry Fox Program (to J. H.). Additional support was provided by Public Health Service awards P30 CA68485 for the Vanderbilt-Ingram Cancer Center and P60 DK20593 for the Vanderbilt Diabetes Research and Training Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and supplemental Figs. S1–S7.

¹ These authors contributed equally to this work.

² Supported by a National Sciences and Engineering Research Council of Canada Studentship award.

³ Supported by a Canadian Institutes of Health Research senior investigator award.

⁴ To whom correspondence should be addressed: Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Ave. South, Nashville, TN 37232-2581. Tel.: 615-343-9943; Fax: 615-343-9723; E-mail: terry.dermody{at}vanderbilt.edu.

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