The collaborative efforts of several groups across the globe, including the Riezman lab from UNIGE and member of the NCCR network, were recently reported in e-Life journal. The work reports the role of intracellular sphingosine as a new small molecule effector of lysosomal calcium homeostasis and describes the lysosome as a triggerable calcium store as well as specific transcription factor translocation as a consequence of lysosomal calcium release.
To elucidate new functions of sphingosine (Sph), the authors 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. The results show that Sph accumulates in endosomes/lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging.
The authors 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.
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