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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
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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.

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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.