Format

Send to

Choose Destination
J Cell Sci. 2018 May 21;131(10). pii: jcs213587. doi: 10.1242/jcs.213587.

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

Author information

1
Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada, M5B2K3.
2
The Graduate Program in Molecular Science, Ryerson University, Toronto, ON, Canada, M5B2K3.
3
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
4
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
5
Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, 50 South Drive, Building 50, Room 3537, Bethesda, MD 20892, USA.
6
Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada, M5B2K3 rbotelho@ryerson.ca.

Abstract

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.

KEYWORDS:

Fission; Fusion; Lysosomes; Organelles; Phosphoinositides; Transcription factors

PMID:
29661845
PMCID:
PMC6031331
DOI:
10.1242/jcs.213587
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center