Identification and Characterization of the Molecule Responsible for Lysosomal Ca2+/H+ Exchange in Humans

The release of Ca2+ stored in lysosomes is critical to cell signaling through removal of degraded cargo and transcriptional reprogramming. While lysosomal Ca2+ release can be accounted for by known Ca2+ channels, the process by which Ca2+ is refilled into lysosomes remains poorly understood. Current hypotheses for lysosomal Ca2+ import include a H+ exchange process and direct refilling from the endoplasmic reticulum (ER). Here, using an RNA interference screen in C. elegans, we identify an evolutionarily conserved gene, denoted lcax-1, that facilitates lysosomal Ca2+ import. Lysosomal Ca2+ measurements and functional assays in C. elegans and mammalian cells reveal that the human homolog, LCAX-1, imports Ca2+ pH-dependently into lysosomes. While electrophysiological characteristics of LCAX-1 are consistent with the long sought human lysosomal Ca2+/H+ exchanger, there are notable differences in its sequence and predicted structure compared to classical CAX transporters, none of which are electrogenic. Future work on LCAX-1 should explore these differences, especially its quaternary structure and its stoichiometry of exchange. Defects in many lysosomal Ca2+ channels lead to different neurodegenerative diseases, and knowledge of new Ca2+ importers may provide new avenues to explore the physiology of Ca2+ channels