Intracellular sphingosine releases calcium from lysosomes

• DOI: 10.7554/elife.10616
• Publication Date: 2015-11-27T12:43:35Z
• Authors: Doris Höglinger; Per Haberkant; Auxiliadora Aguil...; Howard Riezman; Forbes D Porter; Frances M Platt; Antony Galione; Carsten Schultz
• Keywords: 0301 basic medicine; autophagy; info:eu-repo/classification/ddc/540; calcium homeostasis; QH301-705.5; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Science; Q; R; two-pore channel 1; Cell Biology; lipid localization; 03 medical and health sciences; Sphingosine; ddc:540; Medicine; Humans; caged compound; Calcium; Calcium Channels; Biology (General); Lysosomes; Niemann-Pick type C; Cells, Cultured

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.