A TRP Channel in the Lysosome Regulates Large Particle Phagocytosis via Focal Exocytosis

来自 dx.doi.org

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作者：

M Samie，W Xiang，X Zhang，A Goschka，X Li，X Cheng，E Gregg，M Azar，Z Yue，A Garrity

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摘要：

Summary Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here, we identified mucolipin \{TRP\} channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic \{TRPML1\} blockers and are defective in macrophages isolated from \{TRPML1\} knockout mice. Furthermore, \{TRPML1\} overexpression and \{TRPML1\} agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+-dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells invivo.

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关键词：

MUCOLIPIDOSIS TYPE-IV INTRACELLULAR CA2+ STORES PLASMA-MEMBRANE REPAIR PHAGOSOME MATURATION HUMAN NEUTROPHILS MACROPHAGES CALCIUM SECRETION DYNAMICS