Intracellular sphingosine releases calcium from lysosomes

Sphingosine is a small fat molecule that has been suggested to act as a signal inside cells. Individuals with a rare neurodegenerative disease called Niemann-Pick disease type C accumulate sphingosine and other fat molecules in cell compartments called lysosomes. Intriguingly, this fat accumulation is accompanied by an altered movement of calcium ions in and out of lysosomes. In healthy cells, an increase in calcium ion levels can trigger a process called autophagy, in which proteins and other cell components are destroyed in a controlled manner. This is thought to be caused by the release of calcium ions from lysosomes, which stimulates a protein called TFEB to move into the nucleus of the cell to activate genes involved in autophagy. Two proteins on the surface of lysosomes called TPC1 and TPC2 are believed to act as channels that can release calcium ions from lysosomes. However, it was not clear how sphingosine could disrupt calcium ion movements in patients with Niemann-Pick disease type C. Here, Hoeglinger et al. have used a new approach to understand how calcium ions and sphingosine are linked in both healthy and diseased cells. The experiments use a form of sphingosine called “caged sphingosine” that is only activated when it is exposed to a flash of light, which makes it possible to increase the levels of this molecule in cells in a precise way. Hoeglinger et al. found that sphingosine triggered the release of calcium ions from lysosomes. This release required the TPC1 protein and resulted in TFEB moving into the cell nucleus. Further experiments confirm that sphingosine accumulates in the lysosomes of cells taken from patients with Niemann-Pick disease type C. In these cells, the activation of caged sphingosine resulted in a much smaller release of calcium ions from lysosomes than that observed in healthy cells. Together, Hoeglinger et al.’s findings show that sphingosine acts as a signal to trigger the release of calcium ions from lysosomes, which in turn promotes autophagy. The next challenge is to find out exactly how sphingosine opens the calcium ion channels.