Lysosomal ATP Transporter SLC17A9 Controls Cell Viability via Regulating Cathepsin D

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7 Citations (Scopus)

Abstract

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, a lysosomal cysteine protease, is not altered by SLC17A9 deficiency, and Cathepsin B overexpression does not rescue lysosomal dysfunction and cell death induced by SLC17A9 deficiency. Our data suggest that lysosomal ATP and SLC17A9 play critical roles in lysosomal function and cell viability by regulating Cathepsin D activity.

Original languageEnglish
Article number887
JournalCells
Volume11
Issue number5
DOIs
Publication statusPublished - Mar 1 2022

Bibliographical note

Funding Information:
Acknowledgments: This work was supported by CIHR grant (MOP-119349), CIHR project grant (PJT-156102), and CFI Leaders Opportunity Fund-Funding for research infrastructure (29291). We thank François Darchen for Cathepsin D-mRFP, Hyeryun Choe for hCathepsin B (Addgene plasmid 11249), and Shawn Ferguson for TFEB (Addgene plasmid 38119). We appreciate the encouragement and helpful comments from other members of the Dong laboratory.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

ASJC Scopus Subject Areas

  • General Medicine

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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Huang, P., Cao, Q., Xu, M., & Dong, X. P. (2022). Lysosomal ATP Transporter SLC17A9 Controls Cell Viability via Regulating Cathepsin D. Cells, 11(5), Article 887. https://doi.org/10.3390/cells11050887