Activation of Antibacterial Autophagy by NADPH Oxidases

Autophagy plays an important role in immunity to microbial pathogens. The autophagy system can target bacteria in phagosomes, promoting phagosome maturation and preventing pathogen escape into the cytosol. Recently, Toll-like receptor (TLR) signaling from phagosomes was found to initiate their targe...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-04, Vol.106 (15), p.6226-6231
Main Authors: Huang, Ju, Canadien, Veronica, Lam, Grace Y., Steinberg, Benjamin E., Dinauer, Mary C., Magalhaes, Marco A. O., Glogauer, Michael, Grinstein, Sergio, Brumell, John H., Unanue, Emil R.
Format: Article
Language:English
Subjects:
Animals
Autophagy - immunology
Bacteria
Bacterial proteins
Biological Sciences
Cell Line
Cell lines
COS cells
Epithelial cells
Epithelial Cells - cytology
Epithelial Cells - enzymology
Epithelial Cells - immunology
Epithelial Cells - microbiology
Humans
Macrophages
Mice
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Neutrophils
Oxidases
Oxidation
Pathogens
Phagocytosis
Phagosomes
Phagosomes - immunology
Reactive oxygen species
Reactive Oxygen Species - metabolism
Receptors, Antigen, T-Cell - immunology
Receptors, IgG - immunology
Salmonella typhimurium - immunology
Signal transduction
Signal Transduction - immunology
T cell receptors
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Summary:Autophagy plays an important role in immunity to microbial pathogens. The autophagy system can target bacteria in phagosomes, promoting phagosome maturation and preventing pathogen escape into the cytosol. Recently, Toll-like receptor (TLR) signaling from phagosomes was found to initiate their targeting by the autophagy system, but the mechanism by which TLR signaling activates autophagy is unclear. Here we show that autophagy targeting of phagosomes is not exclusive to those containing TLR ligands. Engagement of either TLRs or the Fey receptors (FcγRs) during phagocytosis induced recruitment of the autophagy protein LC3 to phagosomes with similar kinetics. Both receptors are known to activate the NOX2 NADPH oxidase, which plays a central role in microbial killing by phagocytes through the generation of reactive oxygen species (ROS). We found that NOX2-generated ROS are necessary for LC3 recruitment to phagosomes. Antibacterial autophagy in human epithelial cells, which do not express NOX2, was also dependent on ROS generation. These data reveal a coupling of oxidative and nonoxidative killing activities of the NOX2 NADPH oxidase in phagocytes through autophagy. Furthermore, our results suggest a general role for members of the NOX family in regulating autophagy.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0811045106