Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2.
Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2.
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DOI：
10.1016/j.freeradbiomed.2015.05.043
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发表时间：
2015-11
影响因子：
7.4
通讯作者：
Casola A
中科院分区：
文献类型：
--
作者：
Komaravelli N;Tian B;Ivanciuc T;Mautemps N;Brasier AR;Garofalo RP;Casola A
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 viral-induced inhibition of AOE expression. This study shows that RSV infection induces a progressive reduction in nuclear and total cellular level 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 viral-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 antioxidant airway capacity during infection.
