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Updated: Jun 16, 2026

Measuring Enzymatic Activity of Neurodevelopmental Disorder-Associated Deubiquitylating Enzymes via an In Vitro Ubiquitin Chain Cleavage Assay
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Measuring Enzymatic Activity of Neurodevelopmental Disorder-Associated Deubiquitylating Enzymes via an In Vitro Ubiquitin Chain Cleavage Assay

Published on: September 27, 2024

The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway

Bin Zhao1, Claudia Schlesiger, Maria G Masucci

  • 1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Journal of Cellular and Molecular Medicine
|February 10, 2010
PubMed

Insights

Researchers identified ubiquitin specific protease 4 (USP4) as a novel regulator of the Wnt signalling pathway. Suppressing USP4 activates beta-catenin dependent transcription, offering new therapeutic targets for Wnt-related diseases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The canonical Wnt signalling pathway is crucial for embryonic development and tissue homeostasis.
  • Aberrant Wnt signalling is implicated in developmental disorders and cancer.
  • Identifying novel regulators of Wnt signaling is essential for understanding and treating these conditions.

Purpose of the Study:

  • To screen for novel regulators of the canonical Wnt signalling pathway using a targeted RNA interference library.
  • To investigate the role of deubiquitinating enzymes (DUBs) in Wnt pathway regulation.

Main Methods:

  • Utilized an RNA interference (RNAi) library targeting human deubiquitinating enzymes (DUBs).
  • Performed functional assays to assess the impact of DUB suppression on Wnt signalling.
  • Investigated protein interactions and enzymatic activity of identified regulators.

Main Results:

  • Suppression of ubiquitin specific protease 4 (USP4) leads to activation of beta-catenin dependent transcription.
  • USP4 exhibits dual hydrolyzing activity on K48- and K63-linked polyubiquitin chains.
  • USP4 interacts with Nemo-like kinase (Nlk) and T-cell factor 4 (TCF4), with Nlk promoting USP4 nuclear accumulation and TCF4 being a substrate for USP4-dependent deubiquitination.

Conclusions:

  • USP4 is a novel regulator of the canonical Wnt signalling pathway.
  • USP4's deubiquitinating activity on key Wnt components suggests a role in controlling pathway output.
  • Modulating USP4 expression presents a potential therapeutic strategy for Wnt-related physiological and pathological conditions.

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