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VCP/p97 regulates Beclin-1-dependent autophagy initiation.
Sandra M Hill1,2,3, Lidia Wrobel1,3, Avraham Ashkenazi1,3,4
1Department of Medical Genetics, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK.
Nature Chemical Biology
|January 29, 2021
Summary
The protein VCP/p97 (valosin-containing protein) is a novel regulator of autophagy, essential for initiating the cellular process of autophagosome biogenesis. This discovery offers new insights into cellular waste removal and potential therapeutic targets for neurodegenerative diseases.
Area of Science:
- Cell Biology
- Molecular Biology
- Neuroscience
Background:
- Autophagy is a critical cellular mechanism for clearing damaged proteins and pathogens.
- Upregulation of autophagy shows potential in combating neurodegeneration and infections.
Purpose of the Study:
- To identify novel regulators of autophagosome biogenesis.
- To elucidate the role of VCP/p97 (valosin-containing protein) in autophagy induction.
Main Methods:
- Utilized small-molecule inhibitors targeting VCP ATPase activity.
- Investigated VCP's interaction with Beclin-1 and its effect on deubiquitinase activity.
- Assessed the impact of VCP modulation on the Beclin-1 PI3K complex and PI(3)P production.
Main Results:
- VCP/p97 stabilizes Beclin-1 levels by enhancing ataxin-3's deubiquitinase activity.
- VCP regulates the assembly and activity of the Beclin-1 PI3K complex I, crucial for PI(3)P signaling.
- Inhibition of VCP impairs starvation-induced PI(3)P production and downstream autophagy factor recruitment (WIPI2, ATG16L, LC3).
Conclusions:
- VCP/p97 is a key regulator of early autophagy initiation.
- VCP's ATPase activity is vital for autophagosome biogenesis through Beclin-1 stabilization and PI3K complex regulation.
- Targeting VCP offers a potential strategy for modulating autophagy in diseases.
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