USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK.
Jing Liu1,2, Xiaoping Hu3, Kaixiu Luo3
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
Journal of the American Chemical Society
|April 10, 2024
Summary
Researchers developed new deubiquitinase-targeting chimeras (DUBTACs) using USP7, expanding targeted protein stabilization. These USP7-based DUBTACs effectively stabilize proteins and offer potential therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Deubiquitinase-targeting chimeras (DUBTACs) stabilize proteins, contrasting with targeted protein degradation (TPD).
- Current DUBTAC development relies on OTUB1, using covalent ligands that may impair endogenous OTUB1 function.
Purpose of the Study:
- To explore USP7 as an alternative deubiquitinase for DUBTAC development.
- To create and evaluate USP7-based DUBTACs for protein stabilization.
- To investigate USP7-based DUBTACs for stabilizing AMPK isoforms.
Main Methods:
- Development of USP7-based DUBTACs utilizing noncovalent USP7 ligands.
- Assessment of USP7-DUBTACs for stabilizing the ΔF508-CFTR mutant protein.
- Creation of AMPK DUBTACs using USP7 and evaluation of AMPK isoform stabilization and signaling.
Main Results:
- USP7-based DUBTACs effectively stabilized the ΔF508-CFTR mutant protein, comparable to OTUB1-based DUBTACs.
- The first AMPK DUBTACs were developed using USP7 noncovalent ligands.
- These novel AMPK DUBTACs selectively stabilized different AMPKβ isoforms, enhancing AMPK signaling.
Conclusions:
- USP7 can be effectively utilized for DUBTAC development, broadening the options beyond OTUB1.
- Noncovalent USP7 ligands offer a safer alternative for DUBTAC construction compared to covalent OTUB1 ligands.
- The development of USP7-based AMPK DUBTACs presents new therapeutic avenues for modulating AMPK signaling.
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