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Inhibition of p-IκBα Ubiquitylation by Autophagy-Related Gene 7 to Regulate Inflammatory Responses to Bacterial Infection.
- Source :
- Journal of Infectious Diseases; 12/1/2015, Vol. 212 Issue 11, p1816-1826, 11p
- Publication Year :
- 2015
-
Abstract
- <bold>Background: </bold>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. <bold>Methods: </bold>Expression levels of Atg7, ubiquitin (Ub), and tumor necrosis factor (TNF) α and phosphorylation of IκBα (p-IκBα) were determined with immunoblotting. Ubiquitylation of p-IκBα was determined with immunoprecipitation. <bold>Results: </bold>We noted an interaction between Atg7 and p-IκBα, which was decreased in MH-S after K. pneumoniae infection, whereas the interaction between Ub and p-IκBα was increased. Knock-down of Atg7 with small interfering RNA increased p-IκBα ubiquitylation, promoted nuclear factor κB translocation into the nucleus, and increased the production of TNF-α. Moreover, knock-down of Ub with lentivirus-short hairpin RNA Ub particles decreased binding of p-IκBα to Ub and inhibited TNF-α expression in the primary alveolar macrophages and lung tissue of atg7-knockout mice on K. pneumoniae infection. <bold>Conclusions: </bold>Loss of Atg7 switched binding of p-IκBα from Atg7 to Ub, resulting in increased ubiquitylation of p-IκBα and intensified inflammatory responses against K. pneumoniae. Our findings not only reveal a regulatory role of Atg7 in ubiquitylation of p-IκBα but also indicate potential therapeutic targets for K. pneumoniae control. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00221899
- Volume :
- 212
- Issue :
- 11
- Database :
- Complementary Index
- Journal :
- Journal of Infectious Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 110751587
- Full Text :
- https://doi.org/10.1093/infdis/jiv301