A mechanism of lysosomal calcium entry.

Lysosomal calcium (Ca 2+ ) release is critical to cell signaling and is mediated by well-known lysosomal Ca 2+ channels. Yet, how lysosomes refill their Ca 2+ remains hitherto undescribed. Here, from an RNA interference screen in Caenorhabditis elegans , we identify an evolutionarily conserved gene, lci-1 , that facilitates lysosomal Ca 2+ entry in C. elegans and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca 2+ /H + exchanger, imports Ca 2+ pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca 2+ importer. Defects in lysosomal Ca 2+ channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca 2+ importers may provide previously unidentified avenues to explore the physiology of Ca 2+ channels.