Journal
JOURNAL OF CELL SCIENCE
Volume 131, Issue 10, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.213587
Keywords
Transcription factors; Phosphoinositides; Lysosomes; Organelles; Fusion; Fission
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada
- Early Researcher Award program from Government of Ontario
- Tier II Canada Research Chairs Award
- Ryerson University
- Ontario Graduate Scholarship
- Queen Elizabeth II Graduate Scholarship
- National Institutes of Health [GM24872]
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Lysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects, including embryonic lethality, neurodegeneration and overt inflammation. The reasons for such drastic lysosome enlargement remain unclear. Here, we examined whether biosynthesis and/or fusion-fission dynamics contribute to swelling. First, we show that PIKfyve inhibition activates TFEB, TFE3 and MITF, enhancing lysosome gene expression. However, this did not augment lysosomal protein levels during acute PIKfyve inhibition, and deletion of TFEB and/or related proteins did not impair lysosome swelling. Instead, PIKfyve inhibition led to fewer but enlarged lysosomes, suggesting that an imbalance favouring lysosome fusion over fission causes lysosome enlargement. Indeed, conditions that abated fusion curtailed lysosome swelling in PIKfyve-inhibited cells.
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