Deubiquitinases: from mechanisms to their inhibition by small molecules

Sven M. Lange; Lee A. Armstrong; Yogesh Kulathu

doi:10.1016/j.molcel.2021.10.027

Deubiquitinases: from mechanisms to their inhibition by small molecules

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

MRC PPU

Research output: Contribution to journal › Review article › peer-review

144 Citations (Scopus)

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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 language	English
Pages (from-to)	15-29
Number of pages	15
Journal	Molecular Cell
Volume	82
Issue number	1
Early online date	22 Nov 2021
DOIs	https://doi.org/10.1016/j.molcel.2021.10.027
Publication status	Published - 6 Jan 2022

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Author accepted manuscript
© 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Accepted author manuscript, 4.75 MBLicence: CC BY-NC-ND

Cite this

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title = "Deubiquitinases: from mechanisms to their inhibition by small molecules",

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.",

keywords = "Ubiquitin signalling, ubiquitylation, polyubiquitin, structural biology, enzyme regulation, signal transduction, cancer, infectious disease, COVID-19, DUB inhibitors",

author = "Lange, {Sven M.} and Armstrong, {Lee A.} and Yogesh Kulathu",

note = "Funding Information: We are grateful to Profs. Alessi and Cohen and members of the Kulathu lab, especially Drs. Matthews and McFarland, for critical comments and feedback on this manuscript. This work was supported by the Medical Research Council UK (MC_UU_00018/3), the EMBO Young Investigator Programme, and an ERC starting grant (677623). Y.K. is a Lister Prize fellow. We also thank the creators of the open-source software packages that were used to visualise structures: PyMOL (Schrodinger, 2010), UCSF ChimeraX (Pettersen, 2021), and Illustrate (Goodsell et al. 2019). The authors declare no competing interests. Funding Information: We are grateful to Profs. Alessi and Cohen and members of the Kulathu lab, especially Drs. Matthews and McFarland, for critical comments and feedback on this manuscript. This work was supported by the Medical Research Council UK ( MC_UU_00018/3 ), the EMBO Young Investigator Programme , and an ERC starting grant ( 677623 ). Y.K. is a Lister Prize fellow. We also thank the creators of the open-source software packages that were used to visualise structures: PyMOL ( Schrodinger, 2010 ), UCSF ChimeraX ( Pettersen, 2021 ), and Illustrate ( Goodsell et al., 2019 ). Publisher Copyright: {\textcopyright} 2021",

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AU - Lange, Sven M.

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AU - Kulathu, Yogesh

N1 - Funding Information: We are grateful to Profs. Alessi and Cohen and members of the Kulathu lab, especially Drs. Matthews and McFarland, for critical comments and feedback on this manuscript. This work was supported by the Medical Research Council UK (MC_UU_00018/3), the EMBO Young Investigator Programme, and an ERC starting grant (677623). Y.K. is a Lister Prize fellow. We also thank the creators of the open-source software packages that were used to visualise structures: PyMOL (Schrodinger, 2010), UCSF ChimeraX (Pettersen, 2021), and Illustrate (Goodsell et al. 2019). The authors declare no competing interests. Funding Information: We are grateful to Profs. Alessi and Cohen and members of the Kulathu lab, especially Drs. Matthews and McFarland, for critical comments and feedback on this manuscript. This work was supported by the Medical Research Council UK ( MC_UU_00018/3 ), the EMBO Young Investigator Programme , and an ERC starting grant ( 677623 ). Y.K. is a Lister Prize fellow. We also thank the creators of the open-source software packages that were used to visualise structures: PyMOL ( Schrodinger, 2010 ), UCSF ChimeraX ( Pettersen, 2021 ), and Illustrate ( Goodsell et al., 2019 ). Publisher Copyright: © 2021

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N2 - 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.

AB - 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.

KW - Ubiquitin signalling

KW - ubiquitylation

KW - polyubiquitin

KW - structural biology

KW - enzyme regulation

KW - signal transduction

KW - cancer

KW - infectious disease

KW - COVID-19

KW - DUB inhibitors

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DO - 10.1016/j.molcel.2021.10.027

M3 - Review article

C2 - 34813758

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VL - 82

SP - 15

EP - 29

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

Deubiquitinases: from mechanisms to their inhibition by small molecules

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

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Regulation of Lymphocyte Biology by Ubiquitin and Ubiquitin like Modifiers RELYUBL (Starting Grant)

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Deubiquitinases: from mechanisms to their inhibition by small molecules

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Regulation of Lymphocyte Biology by Ubiquitin and Ubiquitin like Modifiers RELYUBL (Starting Grant)

Cite this