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USP10 strikes down β-catenin by dual-wielding deubiquitinase activity and phase separation potential

Yinuo Wang1, Aihua Mao2, Jingwei Liu3

  • 1College of Life and Health Science, Northeastern University, Shenyang 110819, China.

Cell Chemical Biology
|August 23, 2023
PubMed

Insights

USP10 deubiquitinase regulates Wnt/β-catenin signaling. It stabilizes Axin1 via deubiquitination and promotes phase separation, suppressing β-catenin in development, homeostasis, and colorectal cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Wnt/β-catenin signaling is vital for development, homeostasis, and cancer.
  • Identifying regulators of this pathway is crucial for basic and translational research.

Purpose of the Study:

  • To identify novel regulators of Wnt/β-catenin signaling.
  • To elucidate the mechanism by which USP10 modulates this pathway.

Main Methods:

  • Protein screening to identify modulators.
  • Biochemical assays to determine deubiquitination activity.
  • Co-immunoprecipitation and phase separation assays.
  • In vivo studies in embryonic development and colorectal cancer models.

Main Results:

  • USP10 was identified as a critical modulator of β-catenin.
  • USP10 stabilizes Axin1 via K48-linked deubiquitination.
  • USP10 physically tethers Axin1 and β-catenin, promoting phase separation for β-catenin suppression.
  • USP10's dual functions (enzymatic and physical) regulate embryonic development and intestinal homeostasis.
  • USP10 suppresses colorectal cancer growth, correlating with Wnt/β-catenin levels.

Conclusions:

  • USP10 exhibits a dual-regulating mechanism (enzyme-dependent and -independent) against Wnt/β-catenin signaling.
  • These functions are context-dependent and operate in parallel.
  • USP10 represents a potential therapeutic target for Wnt/β-catenin-driven diseases.
Keywords:
USP10Wnt/β-cateninphase separationubiquitination

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