TMEM165 acts as a proton-activated Ca2+importer in lysosomes

Abstract

SummaryLysosomal 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 RNAi screen, we identify an evolutionarily conserved gene,lci-1, that facilitates lysosomal Ca2+entry inC. elegansand in mammalian cells. Its human homolog TMEM165, previously designated as a Golgi-resident Ca2+/H+exchanger (CAX), has a minor lysosomal population of unknown function. Using genetics, lysosomal Ca2+imaging and electrophysiology, we show that TMEM165 acts as a proton-activated, lysosomalCa2+importer in lysosomes. Defects in lysosomal Ca2+channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca2+importers may provide new avenues to explore the physiology of Ca2+channels.