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Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical

Nazar Mashtalir1, Salima Daou1, Haithem Barbour1

  • 1Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.

Molecular Cell
|April 8, 2014
PubMed

Insights

The ubiquitin-conjugating enzyme UBE2O targets the tumor suppressor BAP1 for cytoplasmic sequestration, a process critical for cell proliferation and tumor suppression. Disrupting this balance through cancer mutations impairs BAP1 function.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor BAP1 (BRCA1-associated protein 1) plays a role in cell proliferation, but its regulatory mechanisms are not fully understood.
  • Understanding how BAP1's function is controlled is crucial for cancer research and developing targeted therapies.

Purpose of the Study:

  • To elucidate the mechanism by which the ubiquitin-conjugating enzyme UBE2O regulates BAP1.
  • To investigate the role of BAP1 autodeubiquitination in tumor suppression and its disruption in cancer.
  • To explore the broader implications of UBE2O in regulating chromatin-associated proteins and nuclear trafficking.

Main Methods:

  • Investigated the interaction between UBE2O and BAP1 using biochemical assays.
  • Analyzed the effect of UBE2O-mediated ubiquitination on BAP1 localization.
  • Studied cancer-derived BAP1 mutations to assess their impact on autodeubiquitination and localization.
  • Examined the role of UBE2O and BAP1 in adipogenesis.
  • Identified UBE2O target sequences and validated ubiquitination of chromatin remodeling factors.

Main Results:

  • UBE2O multi-monoubiquitinates BAP1's nuclear localization signal, causing cytoplasmic sequestration.
  • BAP1 autodeubiquitination, through intramolecular interactions, counteracts UBE2O's effect.
  • Cancer-associated BAP1 mutations impair autodeubiquitination, leading to cytoplasmic retention and loss of tumor suppression.
  • UBE2O promotes adipogenesis and BAP1 cytoplasmic localization.
  • UBE2O targets chromatin remodeling factors for ubiquitination, revealing a novel signaling pathway.

Conclusions:

  • UBE2O regulates BAP1 nuclear trafficking via atypical ubiquitination, impacting cell proliferation and tumor suppression.
  • BAP1 autodeubiquitination is essential for its tumor suppressor function, and its disruption in cancer contributes to disease progression.
  • This study uncovers a novel ubiquitin-signaling pathway governing chromatin-associated protein function and nuclear transport.

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