title: Phosphorylated glycosphingolipids essential for cholesterol mobilization in Caenorhabditis elegans.
abstract: The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is indispensable. Here, we present a novel class of C. elegans phosphorylated glycosphingolipids, phosphoethanolamine glucosylceramides (PEGCs), capable of rescuing larval arrest induced by sterol starvation. We describe the total synthesis of a major PEGC species and demonstrate that the PEGC synthetic counterpart suppresses the dauer-constitutive phenotype of Niemann-Pick C1 (NPC1) and DAF-7/TGF-β mutant worms caused by impaired intracellular sterol trafficking. PEGC biosynthesis depends on functional NPC1 and TGF-β, indicating that these proteins control larval development at least partly through PEGC. Furthermore, glucosylceramide deficiency dramatically reduced PEGC amounts. However, the resulting developmental arrest could be rescued by oversaturation of food with cholesterol. Taken together, these data show that PEGC is essential for C. elegans development through its regulation of sterol mobilization.
authors.affiliation: MPI of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Boland
authors.affiliation: Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidt
authors.affiliation: MPI of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Zagoriy
authors.affiliation: MPI of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Julio L
authors.initials: JL
authors.lastname: Sampaio
authors.affiliation: Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Raphael F
authors.identifier: 0000-0002-7493-6691
authors.initials: RF
authors.lastname: Fritsche
authors.affiliation: Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Czerwonka
authors.affiliation: Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Tilo
authors.identifier: 0000-0003-3383-9518
authors.initials: T
authors.lastname: Lübken
authors.affiliation: MPI of Molecular Cell Biology and Genetics, Dresden, Germany.|Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Reimann
authors.affiliation: MPI of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Sider
authors.initials: S
authors.lastname: Penkov
authors.affiliation: Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Knölker
authors.affiliation: MPI of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Teymuras V
authors.initials: TV
authors.lastname: Kurzchalia
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002853:Chromatography, Liquid; D006028:Glycosphingolipids / Q000378:metabolism*; D013058:Mass Spectrometry; D015394:Molecular Structure; D009154:Mutation; D010766:Phosphorylation
chemical_list: D006028:Glycosphingolipids; D002784:Cholesterol