title: Coupling between endocytosis and sphingosine kinase 1 recruitment.
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.
authors.affiliation: 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].
authors.forename: Hongying
authors.initials: H
authors.lastname: Shen
authors.affiliation: 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].
authors.forename: Francesca
authors.initials: F
authors.lastname: Giordano
authors.affiliation: 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.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 1] Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA [2].
authors.forename: Jason
authors.initials: J
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Ira
authors.initials: I
authors.lastname: Milosevic
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Yao
authors.affiliation: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Baumgart
authors.affiliation: Zilkha Neurogenetic Institute, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Sieburth
authors.affiliation: 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.
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000818:Animals; D019556:COS Cells; D002107:Caenorhabditis / Q000201:enzymology / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000032:analysis; D004705:Endocytosis / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017421:Sequence Analysis; D000099157:Sphingosine Kinase
chemical_list: D002784:Cholesterol; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase