Huang Ju, Canadien Veronica, Lam Grace Y, Steinberg Benjamin E, Dinauer Mary C, Magalhaes Marco A O, Glogauer Michael, Grinstein Sergio, Brumell John H
Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6226-31. doi: 10.1073/pnas.0811045106. Epub 2009 Apr 1.
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 Fcgamma receptors (FcgammaRs) 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.
自噬在针对微生物病原体的免疫中发挥着重要作用。自噬系统可靶向吞噬小体中的细菌，促进吞噬小体成熟并防止病原体逃逸到细胞质中。最近，发现来自吞噬小体的Toll样受体（TLR）信号传导启动了自噬系统对它们的靶向作用，但TLR信号传导激活自噬的机制尚不清楚。在此我们表明，吞噬小体的自噬靶向并不局限于那些含有TLR配体的吞噬小体。吞噬过程中TLR或Fcγ受体（FcγR）的激活以相似的动力学诱导自噬蛋白LC3募集到吞噬小体。已知这两种受体均能激活NOX2 NADPH氧化酶，该酶通过产生活性氧（ROS）在吞噬细胞杀灭微生物过程中起核心作用。我们发现NOX2产生的ROS是LC3募集到吞噬小体所必需的。在不表达NOX2的人上皮细胞中，抗菌自噬也依赖于ROS的产生。这些数据揭示了吞噬细胞中NOX2 NADPH氧化酶通过自噬实现氧化和非氧化杀伤活性的耦合。此外，我们的结果表明NOX家族成员在调节自噬方面具有普遍作用。
