Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate

Nature. 2013 Jul 11;499(7457):233-7. doi: 10.1038/nature12360. Epub 2013 Jul 3.

Abstract

Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic. Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits. No phosphatidylinositol other than PI(4,5)P2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol-3-phosphates(PI(3)P). How phosphatidylinositol conversion from PI(4,5)P2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) by class II phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P2 or PI(3)K C2α impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P2 by PI(3)K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P2 in endocytosis and unravel a novel discrete function of PI(3,4)P2 in a central cell physiological process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Class II Phosphatidylinositol 3-Kinases / metabolism
  • Clathrin-Coated Vesicles / metabolism
  • Endocytosis*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism
  • Sorting Nexins / metabolism
  • Time Factors

Substances

  • Phosphatidylinositol Phosphates
  • SNX9 protein, human
  • Sorting Nexins
  • phosphatidylinositol 3,4-diphosphate
  • Class II Phosphatidylinositol 3-Kinases
  • Phosphoric Monoester Hydrolases
  • phosphatidylinositol-3,4-bisphosphate 4-phosphatase