Journal
FEBS LETTERS
Volume 596, Issue 11, Pages 1412-1423Publisher
WILEY
DOI: 10.1002/1873-3468.14353
Keywords
ALS; ATP; FUS; liquid-liquid phase separation; VCP
Funding
- Uehara Memorial Foundation
- Kato Memorial Bioscience Foundation
- Nakabayashi Trust for ALS Research, Tokyo, Japan
- JSPS
- National Research Foundation of Korea (NRF) under the Japan-Korea Basic Scientific Corporation
- [19K16259]
- [19H03168]
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The presence of valosin-containing protein (VCP) in FUS granules plays a role in regulating their stability, with VCP consuming ATP to reduce ATP concentrations in the granules. Initial colocalization of VCP stabilizes the granules, while prolonged colocalization destabilizes the granules.
Fused in sarcoma (FUS), a DNA/RNA-binding protein, undergoes liquid-liquid phase separation to form granules in cells. Aberrant FUS granulation is associated with neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We found that FUS granules contain a multifunctional AAA ATPase, valosin-containing protein (VCP), which is known as a key regulator of protein degradation. FUS granule stability depends on ATP concentrations in cells. VCP ATPase changes the FUS granule stability time-dependently by consuming ATP to reduce its concentrations in the granules: VCPs in de novo FUS granules stabilize the granules, while long-lasting VCP colocalization destabilizes the granules. The proteolysis-promoting function of VCP may subsequently dissolve the unstabilized granules. We propose that VCP colocalized to the FUS granules acts as a timer to limit the residence time of the granules in cells.
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