title: Intracellular sphingosine releases calcium from lysosomes.
abstract: To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Höglinger
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Per
authors.initials: P
authors.lastname: Haberkant
authors.affiliation: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors.forename: Auxiliadora
authors.initials: A
authors.lastname: Aguilera-Romero
authors.affiliation: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors.forename: Howard
authors.initials: H
authors.lastname: Riezman
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism*; D013110:Sphingosine / Q000378:metabolism*; D000097903:Two-Pore Channels
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002118:Calcium; D015220:Calcium Channels; D013110:Sphingosine; C064972:TFEB protein, human; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels
keywords: Niemann-Pick type C; autophagy; caged compound; calcium homeostasis; cell biology; human; human biology; lipid localization; medicine; mouse; two-pore channel 1