Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence

DOI PDF PDF Web Site 被引用文献5件
  • Christopher H. Choy
    Ryerson University 1 Department of Chemistry and Biology , , Toronto, ON , Canada , M5B2K3
  • Golam Saffi
    Ryerson University 1 Department of Chemistry and Biology , , Toronto, ON , Canada , M5B2K3
  • Matthew A. Gray
    Ryerson University 1 Department of Chemistry and Biology , , Toronto, ON , Canada , M5B2K3
  • Callen Wallace
    University of Pittsburgh 3 Department of Cell Biology , , Pittsburgh, PA 15261 , USA
  • Roya M. Dayam
    Ryerson University 1 Department of Chemistry and Biology , , Toronto, ON , Canada , M5B2K3
  • Zhen-Yi A. Ou
    Ryerson University 1 Department of Chemistry and Biology , , Toronto, ON , Canada , M5B2K3
  • Guy Lenk
    University of Michigan 4 Department of Human Genetics , , Ann Arbor, MI 48109 , USA
  • Rosa Puertollano
    Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health 5 , 50 South Drive, Building 50, Room 3537, Bethesda, MD 20892 , USA
  • Simon C. Watkins
    University of Pittsburgh 3 Department of Cell Biology , , Pittsburgh, PA 15261 , USA
  • Roberto J. Botelho
    Ryerson University 1 Department of Chemistry and Biology , , Toronto, ON , Canada , M5B2K3

書誌事項

公開日
2018-05-15
権利情報
  • http://www.biologists.com/user-licence-1-1/
DOI
  • 10.1242/jcs.213587
公開者
The Company of Biologists

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<jats:title>ABSTRACT</jats:title> <jats:p>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.</jats:p>

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