title: Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2.
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.
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Narayana
authors.initials: N
authors.lastname: Komaravelli
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Teodora
authors.initials: T
authors.lastname: Ivanciuc
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mautemps
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA; Department of Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch at Galveston, TX 77555, USA.
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch at Galveston, TX 77555, USA; Department of Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, TX 77555, USA. Electronic address: ancasola@utmb.edu.
authors.forename: Antonella
authors.initials: A
authors.lastname: Casola
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D046988:Proteasome Endopeptidase Complex
keywords: Acetylation; Antioxidant enzymes; Nrf2; Oxidative stress; Proteasome; ROS; Respiratory syncytial virus