Respiratory syncytial virus infection induces a reactive oxygen species-MSK1-phospho-Ser-276 RelA pathway required for cytokine expression

Mohammad Jamaluddin, Bing Tian, Istvan Boldogh, Roberto Garofalo, Allan R. Brasier

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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-κB 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-κB-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-κB-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.

Original languageEnglish (US)
Pages (from-to)10605-10615
Number of pages11
JournalJournal of Virology
Volume83
Issue number20
DOIs
StatePublished - Oct 2009

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Respiratory Syncytial Virus Infections
Respiratory Syncytial Viruses
Mitogens
serine
Serine
reactive oxygen species
Reactive Oxygen Species
phosphotransferases (kinases)
cytokines
Phosphotransferases
Cytokines
viruses
infection
Gene Expression
gene expression
phosphorylation
inflammation
Phosphorylation
RNA helicases
RNA Helicases

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Respiratory syncytial virus infection induces a reactive oxygen species-MSK1-phospho-Ser-276 RelA pathway required for cytokine expression. / Jamaluddin, Mohammad; Tian, Bing; Boldogh, Istvan; Garofalo, Roberto; Brasier, Allan R.

In: Journal of Virology, Vol. 83, No. 20, 10.2009, p. 10605-10615.

Research output: Contribution to journalArticle

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