Deubiquitinases: from mechanisms to their inhibition by small molecules

Sven M. Lange, Lee A. Armstrong, Yogesh Kulathu (Lead / Corresponding author)

Research output: Contribution to journalReview articlepeer-review

20 Citations (Scopus)
3 Downloads (Pure)

Abstract

Deubiquitinases (DUBs) are specialized proteases that remove ubiquitin from substrates or cleave within ubiquitin chains to regulate ubiquitylation and therefore play important roles in eukaryotic biology. Dysregulation of DUBs is implicated in several human diseases, highlighting the importance of DUB function. In addition, many pathogenic bacteria and viruses encode and deploy DUBs to manipulate host immune responses and establish infectious diseases in humans and animals. Hence, therapeutic targeting of DUBs is an increasingly explored area that requires an in-depth mechanistic understanding of human and pathogenic DUBs. In this review, we summarize the multiple layers of regulation that control autoinhibition, activation, and substrate specificity of DUBs. We discuss different strategies to inhibit DUBs and the progress in developing selective small-molecule DUB inhibitors. Finally, we propose a classification system of DUB inhibitors based on their mode of action.

Original languageEnglish
Pages (from-to)15-29
Number of pages15
JournalMolecular Cell
Volume82
Issue number1
Early online date22 Nov 2021
DOIs
Publication statusPublished - 6 Jan 2022

Keywords

  • Ubiquitin signalling
  • ubiquitylation
  • polyubiquitin
  • structural biology
  • enzyme regulation
  • signal transduction
  • cancer
  • infectious disease
  • COVID-19
  • DUB inhibitors

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