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

Nat Commun. 2010 Jul 13;1(4):38. doi: 10.1038/ncomms1037.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Cell Membrane / metabolism*
  • Electrophysiology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lysosomes / metabolism*
  • Membrane Proteins
  • Mice
  • Phosphatidylinositol Phosphates / metabolism*
  • Protein Binding
  • TRPM Cation Channels / metabolism*
  • Transient Receptor Potential Channels


  • Intracellular Signaling Peptides and Proteins
  • Mcoln2 protein, mouse
  • Membrane Proteins
  • Phosphatidylinositol Phosphates
  • TRPM Cation Channels
  • Transient Receptor Potential Channels
  • Vac14 protein, mouse
  • phosphatidylinositol 3,5-diphosphate