Coupling between endocytosis and sphingosine kinase 1 recruitment

Nat Cell Biol. 2014 Jul;16(7):652-62. doi: 10.1038/ncb2987. Epub 2014 Jun 15.

Abstract

Genetic studies have suggested a functional link between cholesterol/sphingolipid metabolism and endocytic membrane traffic. Here we show that perturbing the cholesterol/sphingomyelin balance in the plasma membrane results in the massive formation of clusters of narrow endocytic tubular invaginations positive for N-BAR proteins. These tubules are intensely positive for sphingosine kinase 1 (SPHK1). SPHK1 is also targeted to physiologically occurring early endocytic intermediates, and is highly enriched in nerve terminals, which are cellular compartments specialized for exo/endocytosis. Membrane recruitment of SPHK1 involves a direct, curvature-sensitive interaction with the lipid bilayer mediated by a hydrophobic patch on the enzyme's surface. The knockdown of SPHKs results in endocytic recycling defects, and a mutation that disrupts the hydrophobic patch of Caenorhabditis elegans SPHK fails to rescue the neurotransmission defects in loss-of-function mutants of this enzyme. Our studies support a role for sphingosine phosphorylation in endocytic membrane trafficking beyond the established function of sphingosine-1-phosphate in intercellular signalling.

Publication types

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

MeSH terms

  • Animals
  • COS Cells
  • Caenorhabditis / enzymology
  • Caenorhabditis / metabolism
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cholesterol / analysis
  • Endocytosis / physiology*
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Models, Molecular
  • Mutation
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Sequence Analysis

Substances

  • Cholesterol
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase