Mechanisms of Deubiquitinase Specificity and Regulation

Annu Rev Biochem. 2017 Jun 20:86:159-192. doi: 10.1146/annurev-biochem-061516-044916. Epub 2017 May 12.


Protein ubiquitination is one of the most powerful posttranslational modifications of proteins, as it regulates a plethora of cellular processes in distinct manners. Simple monoubiquitination events coexist with more complex forms of polyubiquitination, the latter featuring many different chain architectures. Ubiquitin can be subjected to further posttranslational modifications (e.g., phosphorylation and acetylation) and can also be part of mixed polymers with ubiquitin-like modifiers such as SUMO (small ubiquitin-related modifier) or NEDD8 (neural precursor cell expressed, developmentally downregulated 8). Together, cellular ubiquitination events form a sophisticated and versatile ubiquitin code. Deubiquitinases (DUBs) reverse ubiquitin signals with equally high sophistication. In this review, we conceptualize the many layers of specificity that DUBs encompass to control the ubiquitin code and discuss examples in which DUB specificity has been understood at the molecular level. We further discuss the many mechanisms of DUB regulation with a focus on those that modulate catalytic activity. Our review provides a framework to tackle lingering questions in DUB biology.

Keywords: allosteric regulation; deubiquitinase; linkage specificity; posttranslational modification; substrate-assisted catalysis; ubiquitin code.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Allosteric Regulation
  • Deubiquitinating Enzymes / chemistry
  • Deubiquitinating Enzymes / genetics
  • Deubiquitinating Enzymes / metabolism*
  • Eukaryotic Cells / metabolism*
  • Humans
  • Models, Molecular
  • NEDD8 Protein
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Protein Processing, Post-Translational*
  • Proteolysis
  • Substrate Specificity
  • Sumoylation
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*


  • NEDD8 Protein
  • NEDD8 protein, human
  • Ubiquitin
  • Ubiquitins
  • Ubiquitin-Protein Ligases
  • Deubiquitinating Enzymes