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Journal of Virology, February 2007, p. 1360-1371, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01860-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

I{kappa}B Kinase Subunits {alpha} and {gamma} Are Required for Activation of NF-{kappa}B and Induction of Apoptosis by Mammalian Reovirus{triangledown}

Mark W. Hansberger,1,2 Jacquelyn A. Campbell,1,2 Pranav Danthi,2,3 Pia Arrate,1 Kevin N. Pennington,1 Kenneth B. Marcu,4,5 Dean W. Ballard,1 and Terence S. Dermody1,2,3*

Departments of Microbiology and Immunology,1 Pediatrics,3 Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,2 Department of Biochemistry and Cell Biology, Institute for Cell and Developmental Biology, Stony Brook University, Stony Brook, New York 11794,4 Centro Ricerca Biomedica Applicata, PAD23, St. Orsola University Hospital, University of Bologna, Bologna, Italy 401385

Received 25 August 2006/ Accepted 10 November 2006

Reoviruses induce apoptosis both in cultured cells and in vivo. Apoptosis plays a major role in the pathogenesis of reovirus encephalitis and myocarditis in infected mice. Reovirus-induced apoptosis is dependent on the activation of transcription factor NF-{kappa}B and downstream cellular genes. To better understand the mechanism of NF-{kappa}B activation by reovirus, NF-{kappa}B signaling intermediates under reovirus control were investigated at the level of Rel, I{kappa}B, and I{kappa}B kinase (IKK) proteins. We found that reovirus infection leads initially to nuclear translocation of p50 and RelA, followed by delayed mobilization of c-Rel and p52. This biphasic pattern of Rel protein activation is associated with the degradation of the NF-{kappa}B inhibitor I{kappa}B{alpha} but not the structurally related inhibitors I{kappa}Bß or I{kappa}B{varepsilon}. Using IKK subunit-specific small interfering RNAs and cells deficient in individual IKK subunits, we demonstrate that IKK{alpha} but not IKKß is required for reovirus-induced NF-{kappa}B activation and apoptosis. Despite the preferential usage of IKK{alpha}, both NF-{kappa}B activation and apoptosis were attenuated in cells lacking IKK{gamma}/Nemo, an essential regulatory subunit of IKKß. Moreover, deletion of the gene encoding NF-{kappa}B-inducing kinase, which is known to modulate IKK{alpha} function, had no inhibitory effect on either response in reovirus-infected cells. Collectively, these findings indicate a novel pathway of NF-{kappa}B/Rel activation involving IKK{alpha} and IKK{gamma}/Nemo, which together mediate the expression of downstream proapoptotic genes in reovirus-infected cells.

* Corresponding author. Mailing address: Lamb Center for Pediatric Research, D7235 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 343-9943. Fax: (615) 343-9723. E-mail: terry.dermody{at}vanderbilt.edu.

{triangledown} Published ahead of print on 22 November 2006.

Journal of Virology, February 2007, p. 1360-1371, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01860-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Clarke, P., Beckham, J. D., Leser, J. S., Hoyt, C. C., Tyler, K. L. (2009). Fas-Mediated Apoptotic Signaling in the Mouse Brain following Reovirus Infection. J. Virol. 83: 6161-6170 [Abstract] [Full Text]  
  • Danthi, P., Kobayashi, T., Holm, G. H., Hansberger, M. W., Abel, T. W., Dermody, T. S. (2008). Reovirus Apoptosis and Virulence Are Regulated by Host Cell Membrane Penetration Efficiency. J. Virol. 82: 161-172 [Abstract] [Full Text]  
  • Holm, G. H., Zurney, J., Tumilasci, V., Leveille, S., Danthi, P., Hiscott, J., Sherry, B., Dermody, T. S. (2007). Retinoic Acid-inducible Gene-I and Interferon-beta Promoter Stimulator-1 Augment Proapoptotic Responses Following Mammalian Reovirus Infection via Interferon Regulatory Factor-3. J. Biol. Chem. 282: 21953-21961 [Abstract] [Full Text]  


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