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USP39-Mediated Non-Proteolytic Control of ETS2 Suppresses Nuclear Localization and Activity

Yunsik Choi1, Yuri Lee1, Jin Seo Kim1

  • 1Department of Life Sciences, Sogang University, Seoul 04107, Republic of Korea.

Biomolecules
|October 28, 2023
PubMed

Insights

Researchers discovered that USP39, a deubiquitinase, binds to ETS2 (a transcription factor) and suppresses its activity by reducing its nuclear localization. This interaction offers potential therapeutic strategies for ETS2-related cancers.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • ETS2, an ETS family transcription factor, regulates critical cellular processes like proliferation and apoptosis.
  • Aberrant ETS2 activation is linked to various human cancers, making it a significant therapeutic target.
  • Understanding ETS2 regulation and interactions is key to developing targeted cancer therapies.

Purpose of the Study:

  • To identify novel regulatory partners of the ETS2 transcription factor.
  • To investigate the functional consequences of the interaction between ETS2 and its binding partners.
  • To explore the potential of targeting the ETS2-interacting protein complex in cancer therapy.

Main Methods:

  • Screening of a human deubiquitinase (DUB) library using binding assays.
  • Co-immunoprecipitation and domain mapping to confirm USP39-ETS2 interaction.
  • Western blotting and reporter assays to assess ETS2 deubiquitination and transcriptional activity.
  • Immunofluorescence microscopy to evaluate ETS2 nuclear localization.

Main Results:

  • USP39 was identified as a novel ETS2-binding DUB.
  • USP39 interacts with ETS2 via their amino-terminal regions, independent of specific domains.
  • USP39 deubiquitinates ETS2 but does not affect its protein stability.
  • USP39 significantly suppresses ETS2 transcriptional activity and reduces its nuclear localization.

Conclusions:

  • USP39 acts as a negative regulator of ETS2 function.
  • The interaction between USP39 and ETS2 influences ETS2 transcriptional activity and subcellular localization.
  • Targeting the USP39-ETS2 interaction may offer a novel therapeutic strategy for ETS2-driven cancers.
Keywords:
ETS2USP39deubiquitinasetranscription factor

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