PI(3,5)P2 controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome

Xian-ping Dong, Dongbiao Shen, Xiang Wang, Taylor Dawson, Xinran Li, Qi Zhang, Xiping Cheng, Yanling Zhang, Lois S. Weisman, Markus Delling and Haoxing Xu ()
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Xian-ping Dong: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Dongbiao Shen: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Xiang Wang: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Taylor Dawson: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Xinran Li: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Qi Zhang: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Xiping Cheng: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University
Yanling Zhang: University of Michigan
Lois S. Weisman: University of Michigan
Markus Delling: Children's Hospital Boston
Haoxing Xu: Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University

Nature Communications, 2010, vol. 1, issue 1, 1-11

Abstract: Abstract Membrane fusion and fission events in intracellular trafficking are controlled by both intraluminal Ca2+ release and phosphoinositide (PIP) signalling. However, the molecular identities of the Ca2+ 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)P2, an endolysosome-specific PIP, binds and activates endolysosome-localized mucolipin transient receptor potential (TRPML) channels with specificity and potency. Both PI(3,5)P2-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)P2-deficient mouse fibroblasts is suppressed by overexpression of TRPML1. Notably, this PI(3,5)P2-dependent regulation of TRPML1 is evolutionarily conserved. In budding yeast, hyperosmotic stress induces Ca2+ release from the vacuole. In this study, we show that this release requires both PI(3,5)P2 production and a yeast functional TRPML homologue. We propose that TRPMLs regulate membrane trafficking by transducing information regarding PI(3,5)P2 levels into changes in juxtaorganellar Ca2+, thereby triggering membrane fusion/fission events.

Date: 2010
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DOI: 10.1038/ncomms1037

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