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.

journal_name

Elife

journal_title

eLife

authors

Höglinger D,Haberkant P,Aguilera-Romero A,Riezman H,Porter FD,Platt FM,Galione A,Schultz C

doi

10.7554/eLife.10616

subject

Has Abstract

pub_date

2015-11-27 00:00:00

issn

2050-084X

journal_volume

4

pub_type

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