PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome.
Membrane fusion and fission events in intracellular trafficking are controlled by both intraluminal Ca(2+) release and phosphoinositide (PIP) signalling. However, the molecular identities of the Ca(2+) release channels and the target proteins of PIPs are elusive. In this paper, by direct patch-clamping of the endolysosomal membrane, we report that PI(3,5)P(2), an endolysosome-specific PIP, binds and activates endolysosome-localized mucolipin transient receptor potential (TRPML) channels with specificity and potency. Both PI(3,5)P(2)-deficient cells and cells that lack TRPML1 exhibited enlarged endolysosomes/vacuoles and trafficking defects in the late endocytic pathway. We find that the enlarged vacuole phenotype observed in PI(3,5)P(2)-deficient mouse fibroblasts is suppressed by overexpression of TRPML1. Notably, this PI(3,5)P(2)-dependent regulation of TRPML1 is evolutionarily conserved. In budding yeast, hyperosmotic stress induces Ca(2+) release from the vacuole. In this study, we show that this release requires both PI(3,5)P(2) production and a yeast functional TRPML homologue. We propose that TRPMLs regulate membrane trafficking by transducing information regarding PI(3,5)P(2) levels into changes in juxtaorganellar Ca(2+), thereby triggering membrane fusion/fission events.
Dong
Xian-ping
XP
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
Shen
Dongbiao
D
Wang
Xiang
X
Dawson
Taylor
T
Li
Xinran
X
Zhang
Qi
Q
Cheng
Xiping
X
Zhang
Yanling
Y
Weisman
Lois S
LS
Delling
Markus
M
Xu
Haoxing
H
D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism*; D004594:Electrophysiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D050053:TRPM Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels
D047908:Intracellular Signaling Peptides and Proteins; C505823:Mcoln2 protein, mouse; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; C525133:Vac14 protein, mouse; C106336:phosphatidylinositol 3,5-diphosphate
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