title: A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis.
abstract: 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 in vivo.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Samie
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Goschka
authors.forename: Xinran
authors.initials: X
authors.lastname: Li
authors.forename: Xiping
authors.initials: X
authors.lastname: Cheng
authors.forename: Evan
authors.initials: E
authors.lastname: Gregg
authors.forename: Marlene
authors.initials: M
authors.lastname: Azar
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhuo
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Garrity
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.forename: Susan
authors.initials: S
authors.lastname: Slaugenhaupt
authors.forename: Jim
authors.initials: J
authors.lastname: Pickel
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Zolov
authors.forename: Lois S
authors.initials: LS
authors.lastname: Weisman
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.forename: Steve
authors.initials: S
authors.lastname: Titus
authors.forename: Marthe
authors.initials: M
authors.lastname: Bryant-Genevier
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Marugan
authors.initials: M
authors.lastname: Juan
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Haoxing
authors.initials: H
authors.lastname: Xu
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000235:genetics*; D051379:Mice; D010316:Particle Size; D010587:Phagocytosis / Q000235:genetics*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; D050051:Transient Receptor Potential Channels; C106336:phosphatidylinositol 3,5-diphosphate; D002118:Calcium