Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2

Narayana Komaravelli, Bing Tian, Teodora Ivanciuc, Nicholas Mautemps, Allan R. Brasier, Roberto Garofalo, Antonella Casola

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Respiratory syncytial virus (RSV) is the most important cause of viral acute respiratory tract infections and hospitalizations in children, for which no vaccine or treatment is available. RSV infection in cells, mice, and children leads to rapid generation of reactive oxygen species, which are associated with oxidative stress and lung damage, due to a significant decrease in the expression of airway antioxidant enzymes (AOEs). Oxidative stress plays an important role in the pathogenesis of RSV-induced lung disease, as antioxidants ameliorate clinical disease and inflammation in vivo. The aim of this study is to investigate the unknown mechanism(s) of virus-induced inhibition of AOE expression. RSV infection is shown to induce a progressive reduction in nuclear and total cellular levels of the transcription factor NF-E2-related factor 2 (Nrf2), resulting in decreased binding to endogenous AOE gene promoters and decreased AOE expression. RSV induces Nrf2 deacetylation and degradation via the proteasome pathway in vitro and in vivo. Histone deacetylase and proteasome inhibitors block Nrf2 degradation and increase Nrf2 binding to AOE endogenous promoters, resulting in increased AOE expression. Known inducers of Nrf2 are able to increase Nrf2 activation and subsequent AOE expression during RSV infection in vitro and in vivo, with significant amelioration of oxidative stress. This is the first study to investigate the mechanism(s) of virus-induced inhibition of AOE expression. RSV-induced inhibition of Nrf2 activation, due to deacetylation and proteasomal degradation, could be targeted for therapeutic intervention aimed to increase airway antioxidant capacity during infection.

Original languageEnglish (US)
Pages (from-to)391-403
Number of pages13
JournalFree Radical Biology and Medicine
Volume88
Issue numberPart B
DOIs
StatePublished - 2015

Fingerprint

NF-E2-Related Factor 2
Respiratory Syncytial Virus Infections
Viruses
Down-Regulation
Antioxidants
Degradation
Enzymes
Respiratory Syncytial Viruses
Oxidative stress
Oxidative Stress
Chemical activation
Pulmonary diseases
Proteasome Inhibitors
Histone Deacetylase Inhibitors
Transcription factors
Proteasome Endopeptidase Complex
Respiratory Tract Infections
Lung Diseases
Reactive Oxygen Species
Hospitalization

Keywords

  • Acetylation
  • Antioxidant enzymes
  • Nrf2
  • Oxidative stress
  • Proteasome
  • Respiratory syncytial virus
  • ROS

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2. / Komaravelli, Narayana; Tian, Bing; Ivanciuc, Teodora; Mautemps, Nicholas; Brasier, Allan R.; Garofalo, Roberto; Casola, Antonella.

In: Free Radical Biology and Medicine, Vol. 88, No. Part B, 2015, p. 391-403.

Research output: Contribution to journalArticle

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