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• W2161818114 endingPage "1026" @default.
• W2161818114 startingPage "1010" @default.
• W2161818114 abstract "Macrophages internalize and sequester pathogens into a phagosome. Phagosomes then sequentially fuse with endosomes and lysosomes, converting into degradative phagolysosomes. Phagosome maturation is a complex process that requires regulators of the endosomal pathway including the phosphoinositide lipids. Phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2 ), which respectively control early endosomes and late endolysosomes, are both required for phagosome maturation. Inhibition of PIKfyve, which synthesizes PtdIns(3,5)P2 , blocked phagosome-lysosome fusion and abated the degradative capacity of phagosomes. However, it is not known how PIKfyve and PtdIns(3,5)P2 participate in phagosome maturation. TRPML1 is a PtdIns(3,5)P2 -gated lysosomal Ca(2+) channel. Because Ca(2+) triggers membrane fusion, we postulated that TRPML1 helps mediate phagosome-lysosome fusion. Using Fcγ receptor-mediated phagocytosis as a model, we describe our research showing that silencing of TRPML1 hindered phagosome acquisition of lysosomal markers and reduced the bactericidal properties of phagosomes. Specifically, phagosomes isolated from TRPML1-silenced cells were decorated with lysosomes that docked but did not fuse. We could rescue phagosome maturation in TRPML1-silenced and PIKfyve-inhibited cells by forcible Ca(2+) release with ionomycin. We also provide evidence that cytosolic Ca(2+) concentration increases upon phagocytosis in a manner dependent on TRPML1 and PIKfyve. Overall, we propose a model where PIKfyve and PtdIns(3,5)P2 activate TRPML1 to induce phagosome-lysosome fusion." @default.
• W2161818114 created "2016-06-24" @default.
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• W2161818114 date "2015-06-18" @default.
• W2161818114 modified "2023-10-13" @default.
• W2161818114 title "The Phosphoinositide-Gated Lysosomal Ca²⁺Channel, TRPML1, Is Required for Phagosome Maturation" @default.
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• W2161818114 doi "https://doi.org/10.1111/tra.12303" @default.
• W2161818114 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26010303" @default.
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