Modulation of Lysosomal Cl^- Mediates Migration and Apoptosis through the TRPML1 as a Lysosomal Cl^- Sensor

Lysosomes are responsible for protein degradation and clearance in cellular recycling centers. It has been known that the lysosomal chloride level is enriched and involved in the intrinsic lysosomal function. However, the mechanism by which chloride levels can be sensed and that of the chloride-mediated lysosomal function is unknown. In this study, we verified that reduced chloride levels acutely induced lysosomal calcium release through TRPML1 and lysosomal repositioning toward the juxtanuclear region. Functionally, low chloride-induced lysosomal calcium release attenuated cellular migration. In addition, spontaneous exposure to low chloride levels dysregulated lysosomal biogenesis and subsequently induced delayed migration and promoted apoptosis. Two chloride-sensing GXXXP motifs in the TRPML1 were identified. Mutations in the GXXXP motif of TRPML1 did not affect chloride levels, and there were no changes in migratory ability. In this study, we demonstrated that the depletion of chloride induces reformation of the lysosomal calcium pool and subsequently dysregulated cancer progression, which will assist in improving therapeutic strategies for lysosomal accumulation-associated diseases or cancer cell apoptosis.