TMEM184 proteins are Ca 2+ uptake transporters in lysosomes

Lysosomal Ca 2+ release from acidic stores is critical for lysosomal function, yet the molecular identity of the Ca 2+ uptake conduit has remained elusive. We used a Ca 2+ -imaging–based genetic screen of the lysosomal membrane proteome to identify TMEM184 family proteins as lysosomal Ca 2+ transporters (LyCaTs) essential for Ca 2+ uptake and refilling. TMEM184 selectively transported Ca 2+ while excluding monovalent cations. Loss of TMEM184B/C depleted lysosomal Ca 2+ stores, diminished Ca 2+ release, and disrupted lysosomal exocytosis, biogenesis, and membrane repair, thus phenocopying the release channel transient receptor potential mucolipin 1 (TRPML1) deficiency. Moreover, a human TMEM184B mutation associated with a neurodevelopmental disorder compromised lysosomal Ca 2+ transport, and Tmem184b -deficient mice exhibited profound motor impairment. Thus, TMEM184 constitutes the long-sought Ca 2+ uptake and refilling mechanism that governs lysosomal signaling and homeostasis.