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USP7 protects TFEB from proteasome-mediated degradation.
Swati Keshri1, Mariella Vicinanza1, Michael Takla1
1Cambridge Institute for Medical Research, University of Cambridge, CB2 0XY Cambridge, UK; UK Dementia Research Institute, Cambridge Biomedical Campus, Cambridge, UK.
Cell Reports
|October 16, 2024
Summary
Ubiquitin-specific protease 7 (USP7) stabilizes the master regulator transcription factor EB (TFEB) by removing degradation signals. This finding is crucial for understanding TFEB regulation and developing cancer therapies.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy.
- Dysregulation of TFEB is implicated in metabolic abnormalities and certain cancers.
Purpose of the Study:
- To identify novel regulators of TFEB.
- To elucidate the post-translational mechanisms governing TFEB stability and function.
Main Methods:
- Nuclear interactome analysis to identify TFEB-binding proteins.
- Genetic depletion and pharmacological inhibition of USP7.
- Ubiquitination assays to determine USP7's deubiquitinase activity on TFEB.
- Functional assays assessing TFEB-mediated transcriptional activity, autophagy flux, and lysosome biogenesis.
Main Results:
- Ubiquitin-specific protease 7 (USP7) was identified as a key nuclear interactor and post-translational modulator of TFEB.
- USP7 deubiquitinates TFEB at K116, K264, and K274, specifically removing K48-linked polyubiquitination.
- USP7 inhibition leads to TFEB degradation, impaired TFEB transcriptional activity, and altered autophagy and lysosome biogenesis.
- USP7 preserves TFEB stability in both nuclear and cytoplasmic compartments.
Conclusions:
- USP7 acts as a critical deubiquitinase protecting TFEB from proteasomal degradation.
- USP7 plays a vital role in maintaining TFEB-mediated cellular responses, including those to nutrient deprivation.
- The USP7-TFEB axis represents a potential therapeutic target for diseases involving TFEB dysregulation, such as certain cancers.
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