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Regulation of A20 and other OTU deubiquitinases by reversible oxidation

Yogesh Kulathu1, Francisco J Garcia, Tycho E T Mevissen

  • 1Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.

Nature Communications
|March 7, 2013
PubMed

Insights

Ovarian tumour deubiquitinases, key regulators of protein modification, are controlled by reversible cysteine oxidation. This oxidation, a cysteine sulphenic acid intermediate, offers a novel regulatory mechanism for deubiquitinase activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • Protein ubiquitination is a critical post-translational modification regulating numerous cellular processes.
  • Deubiquitinases (DUBs) are enzymes that remove ubiquitin modifications, acting as crucial regulators within the ubiquitin system.
  • Ovarian tumour deubiquitinases (OTDs) are a family of cysteine proteases involved in cellular signaling, but their regulation remains poorly understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms governing ovarian tumour deubiquitinase activity.
  • To elucidate the role of post-translational modifications in OTD function.
  • To identify novel pathways controlling deubiquitinase activity.

Main Methods:

  • High-resolution crystal structures of the catalytic domain of A20 in various oxidation states.
  • Chemical assays to detect cysteine sulphenic acid intermediates.
  • In vitro and cellular experiments using hydrogen peroxide (H2O2) treatment.

Main Results:

  • Ovarian tumour deubiquitinases are susceptible to reversible oxidation at their catalytic cysteine residue.
  • Crystal structures revealed a stabilized cysteine sulphenic acid intermediate in A20.
  • Many OTDs undergo reversible oxidation upon H2O2 treatment, indicating a conserved regulatory mechanism.

Conclusions:

  • Reversible oxidation of the catalytic cysteine is a novel mechanism for regulating ovarian tumour deubiquitinase activity.
  • Cysteine sulphenic acid formation provides a dynamic control point for DUB function.
  • This finding opens new avenues for understanding OTD regulation in cellular signaling pathways.

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