Intracellular sphingosine releases calcium from lysosomes

• Published in: eLife Vol. 4
• Main Authors: Höglinger, Doris, Haberkant, Per, Aguilera-Romero, Auxiliadora, Riezman, Howard, Porter, Forbes D, Platt, Frances M, Galione, Antony, Schultz, Carsten
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27-11-2015; eLife Sciences Publications, Ltd
• Subjects: autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; caged compound; Calcium - metabolism; Calcium Channels - metabolism; calcium homeostasis; Cell Biology; Cells, Cultured; Human Biology and Medicine; Humans; lipid localization; Lysosomes - drug effects; Lysosomes - metabolism; Niemann-Pick type C; Sphingosine - metabolism; two-pore channel 1; caged compound; human biology; mouse; autophagy; cell biology; Niemann-Pick type C; two-pore channel 1; calcium homeostasis; medicine; human; lipid localization
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.10616

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.