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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.

Original publication

DOI

10.1038/ncb2987

Type

Journal article

Journal

Nat Cell Biol

Publication Date

07/2014

Volume

16

Pages

652 - 662

Keywords

Animals, COS Cells, Caenorhabditis, Cell Membrane, Cells, Cultured, Chlorocebus aethiops, Cholesterol, Endocytosis, Fluorescent Antibody Technique, HEK293 Cells, HeLa Cells, Humans, Mice, Models, Molecular, Mutation, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Structure, Tertiary, Sequence Analysis