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Reference: Dong XP, et al. (2010) PI(3,5)P(2) Controls Membrane Traffic by Direct Activation of Mucolipin Ca Release Channels in the Endolysosome.LID - 38 [pii] Nat Commun 1(4)

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Abstract

Membrane fusion and fission in intracellular trafficking is controlled by both intraluminal Ca(2+) release and phosphoinositide signaling. However, the molecular identities of the Ca(2+) release channels and the target proteins of phosphoinositides are elusive. Here, by direct patch-clamping of the endolysosomal membrane, we report that PI(3,5)P(2), an endolysosome-specific phosphoinositide, binds and activates endolysosome-localized mucolipin TRP (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. Here, we show that this release requires both PI(3,5)P(2) production and a yeast functional TRPML homolog. We propose that TRPMLs regulate membrane trafficking by transducing information about PI(3,5)P(2) levels into changes in juxtaorganellar Ca(2+), thereby triggering membrane fusion/fission events.

Reference Type
Journal Article
Authors
Dong XP, Shen D, Wang X, Dawson T, Li X, Zhang Q, Cheng X, Zhang Y, Weisman LS, Delling M, ... Show all
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