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Nat Commun. 2010 Jul 13;1:38. doi: 10.1038/ncomms1037.

PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.

Abstract

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.

KEYWORDS:

Ca2+ release channel; Fab1; PI(3,5)P2; PIKfyve; TRP channel; Whole-endolysosome recording; endosome; lysosome; membrane trafficking; phosphoinositide; type IV Mucolipidosis; vacuole

PMID:
20802798
PMCID:
PMC2928581
DOI:
10.1038/ncomms1037
[Indexed for MEDLINE]
Free PMC Article

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