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Biomolecules
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Deubiquitinating Enzymes in Health and Disease
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Deubiquitinating Enzymes in Health and Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 16141

Special Issue Editors

Prof. Dr. Qingping Dou

E-Mail Website
Guest Editor
Departments of Oncology, Pharmacology, and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
Interests: molecular targeting; cancer prevention and therapy; drug reposition; ubiquitin–proteasome system; natural products; drug discovery
Special Issues, Collections and Topics in MDPI journals
Dr. Xin Chen

E-Mail Website
Guest Editor
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
Interests: ubiquitin–proteasome system; cancer; cell death; metal complex

Special Issue Information

Dear Colleagues,

The approval of the anticancer 20S proteasome inhibitor bortezomib by the US FDA in the treatment of multiple myeloma has validated the ubiquitin proteasome system (UPS) as a target of cancer therapies. Deubiquitinating enzymes (DUBs) are critical UPS components that play an important role in both human health and disease. Indeed, the dysregulation of deubiquitination processes has been linked with cancer and other pathologies. DUBs are essential for the regulation of the stabilization, activity, function, and localization of proteins through removing ubiquitin tags from ubiquitinated target proteins. Specifically, the degradation of target proteins by the proteasome is facilitated by ubiquitination, which can be reversed by DUBs. DUBs regulate a variety of signaling cascades in cellular processes (e.g., cell proliferation, cell death, and DNA damage). Thus, the targeting of DUBs has emerged as a novel strategy to improve current therapies for treating cancer, neurodegenerative disease and other conditions, and for sensitizing diseased cells that are resistant to frontline therapies.

This Special Issue of Biomolecules will focus on: (i) recent advances in the involvement of DUBs in human diseases, including but not limited to cancer and neurodegenerative disease; (ii) the development of novel synthetic and natural small molecules or the repurposing of existing drugs as novel DUB inhibitors for therapies, and discussions of the forthcoming challenges in the clinical applications of DUB inhibitors; (iii) findings on new mechanisms of the regulation and pathways of DUBs; (iv) new probes for measuring the activity of DUBs and the potential clinical applications; and (v) discovery of DUB-targeting chimeras (DUBTACs) to regulate the stability of the proteins of interest and the prospective clinical potential. In this Special Issue we aim to publish both research and review articles addressing novelties and overviews of DUBs and related research. We encourage you to submit your manuscripts that fit these objectives and the previously stated topics of this Special Issue.

Dr. Q. Ping Dou
Dr. Xin Chen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • deubiquitinase
  • ubiquitin
  • proteasome
  • protein degradation
  • protein stability

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Published Papers (6 papers)

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Research

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31 pages, 5364 KiB  
Article
DUBing Primary Tumors of the Central Nervous System: Regulatory Roles of Deubiquitinases
by Thomas Klonisch, Susan E. Logue, Sabine Hombach-Klonisch and Jerry Vriend
Biomolecules 2023, 13(10), 1503; https://doi.org/10.3390/biom13101503 - 10 Oct 2023
Cited by 1 | Viewed by 2066
Abstract
The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/or mark ubiquitinated proteins for proteasomal degradation but deubiquitinases [...] Read more.
The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/or mark ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors. Full article
(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)
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Graphical abstract

16 pages, 4366 KiB  
Article
USP39-Mediated Non-Proteolytic Control of ETS2 Suppresses Nuclear Localization and Activity
by Yunsik Choi, Yuri Lee, Jin Seo Kim, Peijing Zhang and Jongchan Kim
Biomolecules 2023, 13(10), 1475; https://doi.org/10.3390/biom13101475 - 1 Oct 2023
Viewed by 1996
Abstract
ETS2 is a member of the ETS family of transcription factors and has been implicated in the regulation of cell proliferation, differentiation, apoptosis, and tumorigenesis. The aberrant activation of ETS2 is associated with various human cancers, highlighting its importance as a therapeutic target. [...] Read more.
ETS2 is a member of the ETS family of transcription factors and has been implicated in the regulation of cell proliferation, differentiation, apoptosis, and tumorigenesis. The aberrant activation of ETS2 is associated with various human cancers, highlighting its importance as a therapeutic target. Understanding the regulatory mechanisms and interacting partners of ETS2 is crucial for elucidating its precise role in cellular processes and developing novel strategies to modulate its activity. In this study, we conducted binding assays using a human deubiquitinase (DUB) library and identified USP39 as a novel ETS2-binding DUB. USP39 interacts with ETS2 through their respective amino-terminal regions, and the zinc finger and PNT domains are not required for this binding. USP39 deubiquitinates ETS2 without affecting its protein stability. Interestingly, however, USP39 significantly suppresses the transcriptional activity of ETS2. Furthermore, we demonstrated that USP39 leads to a reduction in the nuclear localization of ETS2. Our findings provide valuable insights into the intricate regulatory mechanisms governing ETS2 function. Understanding the interplay between USP39 and ETS2 may have implications for therapeutic interventions targeting ETS2-related diseases, including cancer, where the dysregulation of ETS2 is frequently observed. Full article
(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)
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13 pages, 2043 KiB  
Article
OTUD7B Activates Wnt Signaling Pathway through the Interaction with LEF1
by Yuri Lee, Hai-long Piao and Jongchan Kim
Biomolecules 2023, 13(6), 1001; https://doi.org/10.3390/biom13061001 - 16 Jun 2023
Cited by 1 | Viewed by 1872
Abstract
The Wnt signaling pathway plays a critical role in regulating normal cellular processes, including proliferation, differentiation, and apoptosis. Dysregulation of Wnt signaling has been implicated in various human diseases, including cancer. β-catenin and LEF1 are key mediators of Wnt signaling, and their dysregulation [...] Read more.
The Wnt signaling pathway plays a critical role in regulating normal cellular processes, including proliferation, differentiation, and apoptosis. Dysregulation of Wnt signaling has been implicated in various human diseases, including cancer. β-catenin and LEF1 are key mediators of Wnt signaling, and their dysregulation is a hallmark of many cancer types. In this study, we aimed to identify the deubiquitinases (DUBs) that regulate the Wnt signaling pathway through the essential component LEF1. Screening candidate DUBs from the human DUB library, we discovered that OTUD7B interacts with LEF1 and activates Wnt signaling. OTUD7B and LEF1 interact with each other through the UBA and HMG domains, respectively. Furthermore, OTUD7B promotes the nuclear localization of LEF1, leading to an increased interaction with β-catenin in the nucleus while not noticeably affecting ubiquitination on LEF1. Using qPCR array analysis, we found that OTUD7B overexpression leads to an upregulation of 75% of the tested Wnt target genes compared to the control. These findings suggest that OTUD7B may serve as a potential therapeutic target in human diseases, including cancers where Wnt signaling is frequently dysregulated. Full article
(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)
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Review

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18 pages, 1921 KiB  
Review
The Emerging Role of Deubiquitinases in Cell Death
by Zhuan Zhou, Xinxin Song, Rui Kang and Daolin Tang
Biomolecules 2022, 12(12), 1825; https://doi.org/10.3390/biom12121825 - 6 Dec 2022
Cited by 3 | Viewed by 3424
Abstract
Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, [...] Read more.
Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, including mono- or polyubiquitination. Functionally, ubiquitination can affect protein abundance, localization, and activity. Like other post-translational modifications, ubiquitination is a dynamic and reversible process mediated by deubiquitinases, a large class of proteases that cleave ubiquitin from proteins and other substrates. The balance between ubiquitination and deubiquitination machinery determines cell fate under stressful conditions. Here, we review the latest advances in our understanding of the role of deubiquitinases in regulating the main types of RCD, including apoptosis, necroptosis, pyroptosis, and ferroptosis. This knowledge may contribute to identifying new protein degradation-related prognostic markers and therapeutic targets for human disease. Full article
(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)
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16 pages, 1389 KiB  
Review
Recent Progress of Deubiquitinating Enzymes in Human and Plant Pathogenic Fungi
by Weixiang Wang, Xuan Cai and Xiao-Lin Chen
Biomolecules 2022, 12(10), 1424; https://doi.org/10.3390/biom12101424 - 4 Oct 2022
Cited by 3 | Viewed by 2177
Abstract
In eukaryotic cells, a large number of proteins are modified by ubiquitination, which leads to proteasomal degradation or change in protein function. The protein ubiquitination process can be reversed by a process called deubiquitination, which plays an important regulatory mechanism in cellular control. [...] Read more.
In eukaryotic cells, a large number of proteins are modified by ubiquitination, which leads to proteasomal degradation or change in protein function. The protein ubiquitination process can be reversed by a process called deubiquitination, which plays an important regulatory mechanism in cellular control. Deubiquitination is catalyzed by deubiquitinating enzymes (DUBs); the cysteine proteases specifically cleave off ubiquitin from ubiquitinated substrates or ubiquitin precursors. Over the past two decades, components of different DUB families have been found to play important roles in both human and plant pathogenic fungi. Given the importance of DUBs for fungal development and virulence, in this review, we concentrate on recent findings and new insights into the roles of DUBs in different fungal pathogens, with a focus on infection-related morphogenesis and virulence, as well as their roles in development and stress response. We also summarize the DUBs-mediated regulatory mechanisms during the above processes. These findings should allow us to develop novel inhibitors to control fungal pathogens. Full article
(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)
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30 pages, 4833 KiB  
Review
Structural and Functional Basis of JAMM Deubiquitinating Enzymes in Disease
by Xin Pan, Sihua Wu, Wenping Wei, Zixuan Chen, Yong Wu and Kaizheng Gong
Biomolecules 2022, 12(7), 910; https://doi.org/10.3390/biom12070910 - 29 Jun 2022
Cited by 12 | Viewed by 3431
Abstract
Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and deubiquitination. As the only known metalloproteinase family of DUBs, JAB1/MPN/Mov34 metalloenzymes (JAMMs) are specifically associated with tumorigenesis and immunological and inflammatory [...] Read more.
Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and deubiquitination. As the only known metalloproteinase family of DUBs, JAB1/MPN/Mov34 metalloenzymes (JAMMs) are specifically associated with tumorigenesis and immunological and inflammatory diseases at multiple levels. The far smaller numbers and distinct catalytic mechanism of JAMMs render them attractive drug targets. Currently, several JAMM inhibitors have been successfully developed and have shown promising therapeutic efficacy. To gain greater insight into JAMMs, in this review, we focus on several key proteins in this family, including AMSH, AMSH-LP, BRCC36, Rpn11, and CSN5, and emphatically discuss their structural basis, diverse functions, catalytic mechanism, and current reported inhibitors targeting JAMMs. These advances set the stage for the exploitation of JAMMs as a target for the treatment of various diseases. Full article
(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)
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