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Biomedicines
Special Issues
Ubiquitylation and Deubiquitylation in Health and Diseases
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Ubiquitylation and Deubiquitylation in Health and Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 3505

Special Issue Editor

Dr. Tadashi Nakagawa

E-Mail Website
Guest Editor
1. Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Japan
2. Division of Cell Proliferation, Tohoku University Graduate School of Medicine, Sendai 980-8576, Japan
Interests: ubiquitin; chromatin; neurodevelopmental disorders; amyotrophic lateral sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the 1980s, ubiquitination and deubiquitination have propelled research on protein modification, uncovering intricate catalytic mechanisms and their functional implications. However, clinically available drugs targeting the ubiquitin system remain limited. In this context, this Special Issue invites original research that broadens the field, as well as review articles that establish a foundation for the continued advancement of ubiquitin research, with a particular focus on the potential translation of these findings into therapeutics, grounded in the roles of proteins in health and disease.

Dr. Tadashi Nakagawa
Guest Editor

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Keywords

  • ubiquitin ligase
  • deubiquitinase
  • health
  • disease
  • therapeutics
  • eukaryotic cells

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Published Papers (5 papers)

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Research

Jump to: Review

12 pages, 1447 KiB  
Article
Proximity Proteomics Reveals USP44 Forms a Complex with BRCA2 in Neuroblastoma Cells and Is Required to Prevent Chromosome Breakage
by Asma Ali, Sajjad Hussain, Tibor Bedekovics, Raymond H. Jeon, Danielle G. May, Kyle J. Roux and Paul J. Galardy
Biomedicines 2024, 12(12), 2901; https://doi.org/10.3390/biomedicines12122901 - 20 Dec 2024
Viewed by 950
Abstract
Background/Objectives: The enzyme ubiquitin-specific protease 44 (USP44) is a deubiquitinating enzyme with identified physiological roles as a tumor suppressor and an oncogene. While some binding partners and substrates are known for USP44, the identification of other interactions may improve our understanding of its [...] Read more.
Background/Objectives: The enzyme ubiquitin-specific protease 44 (USP44) is a deubiquitinating enzyme with identified physiological roles as a tumor suppressor and an oncogene. While some binding partners and substrates are known for USP44, the identification of other interactions may improve our understanding of its role in cancer. We therefore performed a proximity biotinylation study that identified products of several known cancer genes that are associated with USP44, including a novel interaction between BRCA2 and USP44. Methods: We expressed a fusion protein that linked USP44 and mutant Escherichia coli biotin ligase BioID in SH-SY5Y neuroblastoma cells. Control experiments were performed using BioID alone. In duplicate experiments, cells were pulsed with biotin and biotinylated proteins were isolated under denaturing conditions and the proteins were identified by mass spectrometry. The resulting list of proteins were analyzed using Enrichr and cross-referenced with the COSMIC Cancer Gene Census. We validated the association with BRCA2 using immunoprecipitation. The role of USP44 in the Fanconi anemia DNA repair pathway was investigated using chromosome analysis of wild-type or Usp44-knockout cells after exposure to mitomycin C. Results: We identified 146 proteins that were selectively retrieved by the USP44 construct and compared with cells expressing the BioID ligase alone, including 15 gene products encoded by genes on tier 1 of the COSMIC Cancer Gene Census, including BRCA2. The association between USP44 and BRCA2 was validated through immunoprecipitation. We tested the functional role of USP44 in the Fanconi anemia DNA repair pathway through chromosome breakage analysis and found that cells lacking USP44 had a significant increase in chromosome breaks and radial chromosomes. We found that high BRCA2 transcript was correlated with poor survival in neuroblastoma, likely due to its tight association with proliferation in these tumors. Conclusions: Our results identified novel potential binding partners and potential substrates for USP44, including several with direct roles in cancer pathogenesis. Our results identified a novel association between BRCA2 and USP44, and a previously unknown role for USP44 in the Fanconi anemia DNA repair pathway that may contribute to its role in cancer. Full article
(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)
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Review

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21 pages, 635 KiB  
Review
The Emerging Role and Mechanism of E2/E3 Hybrid Enzyme UBE2O in Human Diseases
by Qian Cheng, Zuyin Li, Yongjian Li, Lei Chen, Dingbao Chen and Jiye Zhu
Biomedicines 2025, 13(5), 1082; https://doi.org/10.3390/biomedicines13051082 (registering DOI) - 29 Apr 2025
Abstract
The ubiquitin–proteasome system (UPS) plays a pivotal role in determining protein fate, regulating signal transduction, and maintaining cellular homeostasis. Protein ubiquitination, a key post-translational modification, is orchestrated by the sequential actions of three primary enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin [...] Read more.
The ubiquitin–proteasome system (UPS) plays a pivotal role in determining protein fate, regulating signal transduction, and maintaining cellular homeostasis. Protein ubiquitination, a key post-translational modification, is orchestrated by the sequential actions of three primary enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3), alongside the regulatory influence of deubiquitinases (DUBs) and various cofactors. The process begins with E1, which activates ubiquitin molecules. Subsequently, E2 receives the activated ubiquitin from E1 and transfers it to E3. E3, in turn, recognizes specific target proteins and facilitates the covalent attachment of ubiquitin from E2 to lysine residues on the target protein. Among the E2 enzymes, ubiquitin-conjugating enzyme E2O (UBE2O) stands out as a unique E2–E3 hybrid enzyme. UBE2O directly mediates the ubiquitination of a wide array of substrates, including 5′-AMP-activated protein kinase catalytic subunit alpha-2 (AMPKα2), MAX interactor 1 (Mxi1), and v-maf musculoaponeurotic fibrosarcoma oncogene homolog (c-Maf), among others. In this narrative review, we will explore the structural characteristics of UBE2O and elucidate its molecular functions. Additionally, we will summarize recent advancements in understanding the role of UBE2O in various tumors, Alzheimer’s disease (AD), and metabolic diseases. Finally, we will discuss the potential of targeting UBE2O as a novel therapeutic strategy for the treatment of human diseases. Full article
(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)
17 pages, 922 KiB  
Review
Identification of E3 Ubiquitin Ligase Substrates Using Biotin Ligase-Based Proximity Labeling Approaches
by Koji Matsuhisa, Shinya Sato and Masayuki Kaneko
Biomedicines 2025, 13(4), 854; https://doi.org/10.3390/biomedicines13040854 - 2 Apr 2025
Viewed by 413
Abstract
Ubiquitylation is a post-translational modification originally identified as the first step in protein degradation by the ubiquitin–proteasome system. Ubiquitylation is also known to regulate many cellular processes without degrading the ubiquitylated proteins. Substrate proteins are specifically recognized and ubiquitylated by ubiquitin ligases. It [...] Read more.
Ubiquitylation is a post-translational modification originally identified as the first step in protein degradation by the ubiquitin–proteasome system. Ubiquitylation is also known to regulate many cellular processes without degrading the ubiquitylated proteins. Substrate proteins are specifically recognized and ubiquitylated by ubiquitin ligases. It is necessary to identify the substrates for each ubiquitin ligase to understand the physiological and pathological roles of ubiquitylation. Recently, a promiscuous mutant of a biotin ligase derived from Escherichia coli, BioID, and its variants have been utilized to analyze protein–protein interaction. In this review, we summarize the current knowledge regarding the molecular mechanisms underlying ubiquitylation, BioID-based approaches for interactome studies, and the application of BirA and its variants for the identification of ubiquitin ligase substrates. Full article
(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)
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20 pages, 2553 KiB  
Review
Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders
by Honoka Ashitomi, Tadashi Nakagawa, Makiko Nakagawa and Toru Hosoi
Biomedicines 2025, 13(4), 810; https://doi.org/10.3390/biomedicines13040810 - 28 Mar 2025
Viewed by 384
Abstract
Ubiquitination is a dynamic and tightly regulated post-translational modification essential for modulating protein stability, trafficking, and function to preserve cellular homeostasis. This process is orchestrated through a hierarchical enzymatic cascade involving three key enzymes: the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, and [...] Read more.
Ubiquitination is a dynamic and tightly regulated post-translational modification essential for modulating protein stability, trafficking, and function to preserve cellular homeostasis. This process is orchestrated through a hierarchical enzymatic cascade involving three key enzymes: the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, and the E3 ubiquitin ligase. The final step of ubiquitination is catalyzed by the E3 ubiquitin ligase, which facilitates the transfer of ubiquitin from the E2 enzyme to the substrate, thereby dictating which proteins undergo ubiquitination. Emerging evidence underscores the critical roles of ubiquitin ligases in neurodevelopment, regulating fundamental processes such as neuronal polarization, axonal outgrowth, synaptogenesis, and synaptic function. Mutations in genes encoding ubiquitin ligases and the consequent dysregulation of these pathways have been increasingly implicated in a spectrum of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and attention-deficit/hyperactivity disorder. This review synthesizes current knowledge on the molecular mechanisms underlying neurodevelopment regulated by Cullin-RING ubiquitin ligases—the largest subclass of ubiquitin ligases—and their involvement in the pathophysiology of neurodevelopmental disorders. A deeper understanding of these mechanisms holds significant promise for informing novel therapeutic strategies, ultimately advancing clinical outcomes for individuals affected by neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)
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12 pages, 1408 KiB  
Review
The Role and Mechanism of Deubiquitinase USP7 in Tumor-Associated Inflammation
by Luhong Wang, Yong Zhang, Tao Yu and Huijian Wu
Biomedicines 2024, 12(12), 2734; https://doi.org/10.3390/biomedicines12122734 - 29 Nov 2024
Viewed by 1347
Abstract
Deubiquitinating enzymes are a class of proteases that remove ubiquitin tags from proteins, thereby controlling protein stability and function. Tumor inflammation arises from interactions between tumor cells and their microenvironment, which trigger an inflammatory response. The deubiquitinating enzyme USP7 plays a central role [...] Read more.
Deubiquitinating enzymes are a class of proteases that remove ubiquitin tags from proteins, thereby controlling protein stability and function. Tumor inflammation arises from interactions between tumor cells and their microenvironment, which trigger an inflammatory response. The deubiquitinating enzyme USP7 plays a central role in this process. Research suggests that USP7 may modulate various signaling pathways related to inflammatory responses through its deubiquitinating activity, thereby influencing tumor development and progression, including regulating T cell immune activity, improving macrophage anti-tumor activity, and regulating NF-κB signal pathways. Overall, describing the role and mechanism of USP7 in the tumor inflammatory response is of great importance for elucidating the regulatory mechanism of tumor inflammation and developing new therapeutic strategies. This article mainly reviews the structure, function, role, and mechanism of USP7 in the tumor inflammation response. Full article
(This article belongs to the Special Issue Ubiquitylation and Deubiquitylation in Health and Diseases)
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