biostudies-literatureHuang PCanadian Institutes of Health Research887https://www.ebi.ac.uk/biostudies/studies/S-EPMC8909234biostudies-literatureUnknown11(5)SLC17A9 (solute carrier family 17 member 9) functions as an ATP transporter in lysosomes as well as other secretory vesicles. SLC17A9 inhibition or silence leads to cell death. However, the molecular mechanisms causing cell death are unclear. In this study, we report that cell death induced by SLC17A9 deficiency is rescued by the transcription factor EB (TFEB), a master gene for lysosomal protein expression, suggesting that SLC17A9 deficiency may be the main cause of lysosome dysfunction, subsequently leading to cell death. Interestingly, Cathepsin D, a lysosomal aspartic protease, is inhibited by SLC17A9 deficiency. Heterologous expression of Cathepsin D successfully rescues lysosomal dysfunction and cell death induced by SLC17A9 deficiency. On the other hand, the activity of Cathepsin B,CellsLysosomal ATP Transporter SLC17A9 Controls Cell Viability via Regulating Cathepsin D.PMC8909234MOP-119349PJT-156102Xu MDong XPHuang PCao QfalseLysosomal ATP Transporter SLC17A9 Controls Cell Viability via Regulating Cathepsin D.SLC17A9 (solute carrier family 17 member 9) functions as an ATP transporter in lysosomes as well as other secretory vesicles. SLC17A9 inhibition or silence leads to cell death. However, the molecular mechanisms causing cell death are unclear. In this study, we report that cell death induced by SLC17A9 deficiency is rescued by the transcription factor EB (TFEB), a master gene for lysosomal protein expression, suggesting that SLC17A9 deficiency may be the main cause of lysosome dysfunction, subsequently leading to cell death. Interestingly, Cathepsin D, a lysosomal aspartic protease, is inhibited by SLC17A9 deficiency. Heterologous expression of Cathepsin D successfully rescues lysosomal dysfunction and cell death induced by SLC17A9 deficiency. On the other hand, the activity of Cathepsin B,2022-01-01T00:00:00Z2022 Mar2025-04-05T11:07:24.809Z2025-04-05T11:07:24.809ZS-EPMC89092343526950910.3390/cells11050887