A mechanism of lysosomal calcium entry.

Abstract

Lysosomal calcium (Ca²⁺) release is critical to cell signaling and is mediated by well-known lysosomal Ca²⁺ channels. Yet, how lysosomes refill their Ca²⁺ remains hitherto undescribed. Here, from an RNA interference screen in <i>Caenorhabditis elegans</i>, we identify an evolutionarily conserved gene, <i>lci-1</i>, that facilitates lysosomal Ca²⁺ entry in <i>C. elegans</i> and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca²⁺/H⁺ exchanger, imports Ca²⁺ 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 Ca²⁺ importer. Defects in lysosomal Ca²⁺ channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca²⁺ importers may provide previously unidentified avenues to explore the physiology of Ca²⁺ channels.