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Phagocytosis Enhances Lysosomal and Bactericidal Properties by Activating the Transcription Factor TFEB.


ABSTRACT: Macrophages internalize pathogens through phagocytosis, entrapping them into organelles called phagosomes. Phagosomes then fuse with lysosomes to mature into phagolysosomes, acquiring an acidic and hydrolytic lumen that kills the pathogens. During an ongoing infection, macrophages can internalize dozens of bacteria. Thus, we hypothesized that an initial round of phagocytosis might boost lysosome function and bactericidal ability to cope with subsequent rounds of phagocytosis. To test this hypothesis, we employed Fc?-receptor-mediated phagocytosis and endocytosis, which internalize immunoglobulin G (IgG)-opsonized particles and polyvalent IgG immune complexes, respectively. We report that Fc? receptor activation in macrophages enhances lysosome-based proteolysis and killing of subsequently phagocytosed E. coli compared to naive macrophages. Importantly, we show that Fc? receptor activation causes nuclear translocation of TFEB, a transcription factor that boosts expression of lysosome genes. Indeed, Fc receptor activation is accompanied by increased expression of specific lysosomal proteins. Remarkably, TFEB silencing represses the Fc?-receptor-mediated enhancements in degradation and bacterial killing. In addition, nuclear translocation of TFEB requires phagosome completion and fails to occur in cells silenced for MCOLN1, a lysosomal Ca(2+) channel, suggesting that lysosomal Ca(2+) released during phagosome maturation activates TFEB. Finally, we demonstrate that non-opsonic phagocytosis of E. coli also enhances lysosomal degradation in a TFEB-dependent manner, suggesting that this phenomenon is not limited to Fc? receptors. Overall, we show that macrophages become better killers after one round of phagocytosis and suggest that phagosomes and lysosomes are capable of bi-directional signaling.

SUBMITTER: Gray MA 

PROVIDER: S-EPMC5453720 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Phagocytosis Enhances Lysosomal and Bactericidal Properties by Activating the Transcription Factor TFEB.

Gray Matthew A MA   Choy Christopher H CH   Dayam Roya M RM   Ospina-Escobar Erika E   Somerville Alexander A   Xiao Xuan X   Ferguson Shawn M SM   Botelho Roberto J RJ  

Current biology : CB 20160707 15


Macrophages internalize pathogens through phagocytosis, entrapping them into organelles called phagosomes. Phagosomes then fuse with lysosomes to mature into phagolysosomes, acquiring an acidic and hydrolytic lumen that kills the pathogens. During an ongoing infection, macrophages can internalize dozens of bacteria. Thus, we hypothesized that an initial round of phagocytosis might boost lysosome function and bactericidal ability to cope with subsequent rounds of phagocytosis. To test this hypoth  ...[more]

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