Biomolecules

Editorial

Jump to: Research, Review

4 pages, 213 KiB

Open AccessEditorial

The Multifaceted Role of the Ubiquitin Proteasome System in Pathogenesis and Diseases

by Zane Stekel, Yi Sheng and Wei Zhang

Biomolecules 2022, 12(7), 925; https://doi.org/10.3390/biom12070925 - 1 Jul 2022

Cited by 5 | Viewed by 2126

Abstract

Ubiquitin is a small protein that is conjugated to target proteins to signal a great number of critical biological processes. Impaired ubiquitin signaling and defects in the ubiquitin proteasome system (UPS) surveillance are implicated in many human diseases, including cancer. Characterization of the [...] Read more.

Ubiquitin is a small protein that is conjugated to target proteins to signal a great number of critical biological processes. Impaired ubiquitin signaling and defects in the ubiquitin proteasome system (UPS) surveillance are implicated in many human diseases, including cancer. Characterization of the physiological roles of UPS components and their regulatory mechanisms is therefore vital for the identification of therapeutic targets and the development of tools and paradigms to better understand and treat human diseases. In this Special Issue, we assembled seven original research and review articles to provide insights on the multifaceted role of the UPS in pathogenesis and disease, covering the areas of molecular and cellular mechanisms of UPS enzymes, biochemical and biophysical characterization strategies, drug development, and targeted protein degradation. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

Research

Jump to: Editorial, Review

13 pages, 4976 KiB

Open AccessEditor’s ChoiceArticle

Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain

by Viktoria K. Ilic, Olga Egorova, Ernest Tsang, Milena Gatto, Yi Wen, Yong Zhao and Yi Sheng

Biomolecules 2022, 12(5), 643; https://doi.org/10.3390/biom12050643 - 27 Apr 2022

Cited by 4 | Viewed by 2099

Abstract

The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, [...] Read more.

The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

16 pages, 2492 KiB

Open AccessEditor’s ChoiceArticle

Targeted Degradation of 53BP1 Using Ubiquitin Variant Induced Proximity

by Bayonle Aminu, Julia Fux, Evan Mallette, Nathaniel Petersen and Wei Zhang

Biomolecules 2022, 12(4), 479; https://doi.org/10.3390/biom12040479 - 22 Mar 2022

Cited by 5 | Viewed by 3381

Abstract

In recent years, researchers have leveraged the ubiquitin-proteasome system (UPS) to induce selective degradation of proteins by E3 ubiquitin ligases, which has great potential as novel therapeutics for human diseases, including cancer and neurodegenerative disorders. However, despite extensive efforts, only a handful of [...] Read more.

In recent years, researchers have leveraged the ubiquitin-proteasome system (UPS) to induce selective degradation of proteins by E3 ubiquitin ligases, which has great potential as novel therapeutics for human diseases, including cancer and neurodegenerative disorders. However, despite extensive efforts, only a handful of ~600 human E3 ligases were utilized, and numerous protein–protein interaction surfaces on E3 ligases were not explored. To tackle these problems, we leveraged a structure-based protein engineering technology to develop a multi-domain fusion protein bringing functional E3 ligases to the proximity of a target protein to trigger its proteasomal degradation, which we termed Ubiquitin Variant Induced Proximity (UbVIP). We first generated non-inhibitory synthetic UbV binders for a selected group of human E3 ligases. With these UbVs employed as E3 ligase engagers, we designed a library of UbVIPs targeting a DNA damage response protein 53BP1. We observed that two UbVIPs recruiting RFWD3 and NEDD4L could effectively induce proteasome degradation of 53BP1 in human cell lines. This provides a proof-of-principle that UbVs can act as a means of targeted degradation for nucleus-localized proteins. Our work demonstrated that UbV technology is suitable to develop protein-based molecules for targeted degradation and can help identify novel E3 ligases for future therapeutic development. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

16 pages, 1798 KiB

Open AccessArticle

Rational Development and Characterization of a Ubiquitin Variant with Selectivity for Ubiquitin C-Terminal Hydrolase L3

by Chad S. Hewitt, Chittaranjan Das and Daniel P. Flaherty

Biomolecules 2022, 12(1), 62; https://doi.org/10.3390/biom12010062 - 1 Jan 2022

Cited by 5 | Viewed by 2689

Abstract

There is currently a lack of reliable methods and strategies to probe the deubiquitinating enzyme UCHL3. Current small molecules reported for this purpose display reduced potency and selectivity in cellular assays. To bridge this gap and provide an alternative approach to probe UCHL3, [...] Read more.

There is currently a lack of reliable methods and strategies to probe the deubiquitinating enzyme UCHL3. Current small molecules reported for this purpose display reduced potency and selectivity in cellular assays. To bridge this gap and provide an alternative approach to probe UCHL3, our group has carried out the rational design of ubiquitin-variant activity-based probes with selectivity for UCHL3 over the closely related UCHL1 and other DUBs. The approach successfully produced a triple-mutant ubiquitin variant activity-based probe, UbV^{Q40V/T66K/V70F}-PRG, that was ultimately 20,000-fold more selective for UCHL3 over UCHL1 when assessed by rate of inactivation assays. This same variant was shown to selectively form covalent adducts with UCHL3 in MDA-MB-231 breast cancer cells and no reactivity toward other DUBs expressed. Overall, this study demonstrates the feasibility of the approach and also provides insight into how this approach may be applied to other DUB targets. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

21 pages, 2297 KiB

Open AccessReview

On the Study of Deubiquitinases: Using the Right Tools for the Job

by Cody Caba, Azam Mohammadzadeh and Yufeng Tong

Biomolecules 2022, 12(5), 703; https://doi.org/10.3390/biom12050703 - 14 May 2022

Cited by 6 | Viewed by 3694

Abstract

Deubiquitinases (DUBs) have been the subject of intense scrutiny in recent years. Many of their diverse enzymatic mechanisms are well characterized in vitro; however, our understanding of these enzymes at the cellular level lags due to the lack of quality tool reagents. DUBs [...] Read more.

Deubiquitinases (DUBs) have been the subject of intense scrutiny in recent years. Many of their diverse enzymatic mechanisms are well characterized in vitro; however, our understanding of these enzymes at the cellular level lags due to the lack of quality tool reagents. DUBs play a role in seemingly every biological process and are central to many human pathologies, thus rendering them very desirable and challenging therapeutic targets. This review aims to provide researchers entering the field of ubiquitination with knowledge of the pharmacological modulators and tool molecules available to study DUBs. A focus is placed on small molecule inhibitors, ubiquitin variants (UbVs), and activity-based probes (ABPs). Leveraging these tools to uncover DUB biology at the cellular level is of particular importance and may lead to significant breakthroughs. Despite significant drug discovery efforts, only approximately 15 chemical probe-quality small molecule inhibitors have been reported, hitting just 6 of about 100 DUB targets. UbV technology is a promising approach to rapidly expand the library of known DUB inhibitors and may be used as a combinatorial platform for structure-guided drug design. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

24 pages, 2520 KiB

Open AccessEditor’s ChoiceReview

Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road

by Rachel E. Lacoursiere, Dania Hadi and Gary S. Shaw

Biomolecules 2022, 12(3), 467; https://doi.org/10.3390/biom12030467 - 18 Mar 2022

Cited by 15 | Viewed by 5161

Abstract

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is [...] Read more.

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is complex due to the combinatorial power of ~35 E2 and ~1000 E3 enzymes involved and the multiple lysine residues on ubiquitin that can be used to assemble polyubiquitin chains. Recently, mass spectrometric methods have identified that most enzymes in the ubiquitination cascade can be further modified through acetylation or phosphorylation under particular cellular conditions and altered modifications have been noted in different cancers and neurodegenerative diseases. This review provides a cohesive summary of ubiquitination, acetylation, and phosphorylation sites in ubiquitin, the human E1 enzyme UBA1, all E2 enzymes, and some representative E3 enzymes. The potential impacts these post-translational modifications might have on each protein function are highlighted, as well as the observations from human disease. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

21 pages, 2987 KiB

Open AccessEditor’s ChoiceReview

Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases

by Stephanie Diaz, Kankan Wang, Benita Sjögren and Xing Liu

Biomolecules 2022, 12(3), 416; https://doi.org/10.3390/biom12030416 - 8 Mar 2022

Cited by 9 | Viewed by 4313

Abstract

Maintenance of protein homeostasis is crucial for virtually every aspect of eukaryotic biology. The ubiquitin-proteasome system (UPS) represents a highly regulated quality control machinery that protects cells from a variety of stress conditions as well as toxic proteins. A large body of evidence [...] Read more.

Maintenance of protein homeostasis is crucial for virtually every aspect of eukaryotic biology. The ubiquitin-proteasome system (UPS) represents a highly regulated quality control machinery that protects cells from a variety of stress conditions as well as toxic proteins. A large body of evidence has shown that UPS dysfunction contributes to the pathogenesis of cardiovascular diseases. This review highlights the latest findings regarding the physiological and pathological roles of cullin-RING ubiquitin ligases (CRLs), an essential player in the UPS, in the cardiovascular system. To inspire potential therapeutic invention, factors regulating CRL activities are also discussed. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

20 pages, 1569 KiB

Open AccessFeature PaperReview

Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19

by George Vere, Md Rashadul Alam, Sam Farrar, Rachel Kealy, Benedikt M. Kessler, Darragh P. O’Brien and Adán Pinto-Fernández

Biomolecules 2022, 12(2), 300; https://doi.org/10.3390/biom12020300 - 12 Feb 2022

Cited by 8 | Viewed by 4624

Abstract

Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways [...] Read more.

Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways by removing ubiquitin and/or ISG15 from proteins using a protease called PLpro, but also by interacting with enzymes involved in ubiquitin/ISG15 machinery. These enable viral replication and avoidance of the host immune system. In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host–pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

► Show Figures

Figure 1

Journal Menu

Journal Browser

The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI