Coupling between endocytosis and sphingosine kinase 1 recruitment

  • Nat Cell Biol. 2014 Jul;16(7):652-62. doi: 10.1038/ncb2987.
Hongying Shen  1 ,  Francesca Giordano  1 ,  Yumei Wu  2 ,  Jason Chan  3 ,  Chen Zhu  4 ,  Ira Milosevic  2 ,  Xudong Wu  5 ,  Kai Yao  6 ,  Bo Chen  6 ,  Tobias Baumgart  4 ,  Derek Sieburth  7 ,  Pietro De Camilli  2
Affiliations
  • 1. 1] Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA [3].
  • 2. 1] Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
  • 3. 1] Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA [2].
  • 4. Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 5. Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
  • 6. Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
  • 7. Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
PMID: 24929359 DOI: 10.1038/ncb2987
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.