Mechanisms of regulation and diversification of deubiquitylating enzyme function

Abstract

Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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USP7 as part of non-canonical PRC1.1 is a druggable target in leukemia

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Pseudo-DUBs as allosteric activators and molecular scaffolds of protein complexes

“…Ubiquitylation is a reversible process, and removal of Ub is carried out by deubiquitylating (DUB) enzymes (eraser module). DUB actions allow the cell to produce monomeric Ub, recycle Ub from chains and reverse signalling events resulting from ubiquitylation [6,7] . To date, 99 DUBs have been identified in the human genome, comprising six major structural families, namely (1) the ubiquitin-specific proteases (USPs), (2) the ubiquitin C-terminal hydrolyses (UCHs), (3) the Machado-Joseph domain proteases (Josephins), (4) the ovarian tumour proteases (OTUs), (5) the Jab1/MPN/Mov34 metalloproteases (JAMM/MPNs) and (6) the newly discovered MIU-containing novel DUB family proteases (MINDYs) (Fig.…”