Inhibition Of P-I Kappa B Alpha Ubiquitylation By Autophagy-Related Gene 7 To Regulate Inflammatory Responses To Bacterial Infection
JOURNAL OF INFECTIOUS DISEASES(2015)
摘要
Background. Klebsiella pneumoniae causes serious infections and healthcare burdens in humans. We have previously reported that the deficiency of autophagy-related gene (Atg) 7 in macrophages (murine alveolar macrophage cell line [MH-S]) induced irregular host immunity against K. pneumoniae and worsened pathologic effects in the lung. In the current study, we investigated the molecular mechanism by which Atg7 influenced K. pneumoniae-induced inflammatory responses.Methods. Expression levels of Atg7, ubiquitin (Ub), and tumor necrosis factor (TNF) a and phosphorylation of I kappa B alpha (p-I kappa B alpha) were determined with immunoblotting. Ubiquitylation of p-I kappa B alpha was determined with immunoprecipitation.Results. We noted an interaction between Atg7 and p-I kappa B alpha, which was decreased in MH-S after K. pneumoniae infection, whereas the interaction between Ub and p-I.Ba was increased. Knock-down of Atg7 with small interfering RNA increased p-I.Ba ubiquitylation, promoted nuclear factor kappa B translocation into the nucleus, and increased the production of TNF-alpha. Moreover, knock-down of Ub with lentivirus-short hairpin RNA Ub particles decreased binding of p-I kappa B alpha to Ub and inhibited TNF-a expression in the primary alveolar macrophages and lung tissue of atg7-knockout mice on K. pneumoniae infection.Conclusions. Loss of Atg7 switched binding of p-I.Ba from Atg7 to Ub, resulting in increased ubiquitylation of p-I.Ba and intensified inflammatory responses against K. pneumoniae. Our findings not only reveal a regulatory role of Atg7 in ubiquitylation of p-I.Ba but also indicate potential therapeutic targets for K. pneumoniae control.
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关键词
autophagy, alveolar macrophage, ubiquitin, I kappa B alpha/NF-kappa B pathway, TLR4
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