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.

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