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Journal of Virology, October 2009, p. 10605-10615, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01090-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Respiratory Syncytial Virus Infection Induces a Reactive Oxygen Species-MSK1-Phospho-Ser-276 RelA Pathway Required for Cytokine Expression{triangledown}

Mohammad Jamaluddin,1 Bing Tian,2 Istvan Boldogh,3 Roberto P. Garofalo,4 and Allan R. Brasier1,2*

Institute for Translational Sciences,1 Departments of Medicine,2 Microbiology and Immunology,3 Pediatrics, University of Texas Medical Branch (UTMB), Galveston, Texas 77555-10604

Received 28 May 2009/ Accepted 4 August 2009

Respiratory syncytial virus (RSV) is a human pathogen that induces airway inflammation, at least in part, by modulating gene expression programs in airway epithelial cells. The presence of RSV replication is detected by the intracellular retinoic acid-inducible gene I (RIG-I) RNA helicase that forms a productive signaling complex with the mitochondrion-anchored MAVS protein, resulting in nuclear translocation of the NF-{kappa}B transcription factor. Although nuclear translocation is a prerequisite for activation of the innate inflammatory response, recent studies show that separate pathways governing RelA activation are also required for target gene expression. In this study, we examine the mechanism of RelA phosphorylation and its requirement for RSV-induced gene expression. RSV infection produced a time-dependent RelA phosphorylation on serine (Ser) residues Ser-276 and Ser-536 in parallel with enhanced reactive oxygen species (ROS) stress. Inhibition of RSV-induced ROS inhibited formation of phospho-Ser-276 RelA without affecting phospho-Ser-536 RelA formation. RSV potently induced activation of cytoplasmic mitogen- and stress-related kinase 1 (MSK1) in an ROS-dependent manner. Inhibition of MSK1 using H89 and small interfering RNA knockdown both reduced RSV-induced phospho-Ser-276 RelA formation and expression of a subset of NF-{kappa}B-dependent genes. Direct examination of the role of phospho-Ser-276 in target gene expression by expression of a RelA Ser-276-to-Ala site mutation in RelA–/– mouse embryonic fibroblasts showed that the mutation was unable to mediate RSV-induced NF-{kappa}B-dependent gene expression. We conclude that RSV induces RelA activation in the innate inflammatory response via a pathway separate from that controlling RelA cytoplasmic release, mediated by ROS signaling to cytoplasmic MSK1 activation and RelA Ser-276 phosphorylation.

* Corresponding author. Mailing address: Department of Medicine, Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, TX 77555-1060. Phone: (409) 772-2824. Fax: (409) 772-8709. E-mail: arbrasie{at}utmb.edu

{triangledown} Published ahead of print on 12 August 2009.

Journal of Virology, October 2009, p. 10605-10615, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01090-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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