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Cells
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Advances in Ubiquitination and Deubiquitination Research
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Advances in Ubiquitination and Deubiquitination Research

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 20284

Special Issue Editor

Prof. Dr. Hengbin Wang

E-Mail Website
Guest Editor
Department of Internal Medicine, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Institute, Virginia Commonwealth University, Richmond, VA 23298, USA
Interests: histone H2A deubiquitinase; tumorigenesis; ubiquitination; epigenetic mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ubiquitination, the covalent attachment of the 76 amino acid ubiquitin molecules to substrate proteins, alters the property of target proteins, and this process is essential for virtually all aspects of cellular processes. This post-translational modification occurs through an enzyme cascade involving the E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase enzyme. While there are only two E1 enzymes, there are approximately forty E2 enzymes and over six hundred E3 enzymes in the human genome. The combinations of these enzymes form a complex network and target a wide range of cellular substrates. Moreover, ubiquitin itself contains seven lysine residues that can also serve as receptors for ubiquitin molecules. These different ubiquitin linkages are often associated with distinct properties and significantly increase the functional capacity of the human genome. Furthermore, the levels of ubiquitin on target proteins are counter-balanced by deubiquitination, a process carried out by about one hundred deubiquitinases in the human genome. The ubiquitin-modified proteins are recognized by ubiquitin-interacting proteins, leading to the proteins' distinct fate—most notably, their degradation via the ubiquitin-proteasome pathway. Disturbance of the ubiquitin systems has been associated with various human disorders, including cancer susceptibility.

Prof. Dr. Hengbin B. Wang
Guest Editor

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Keywords

  • ubiquitin
  • ubiquitination
  • deubiquitination
  • ubiquitin-interacting protein
  • ubiquitin linkage

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Published Papers (7 papers)

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Research

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25 pages, 19182 KiB  
Article
Modification of RNF183 via m6A Methylation Mediates Podocyte Dysfunction in Diabetic Nephropathy by Regulating PKM2 Ubiquitination and Degradation
by Dongwei Guo, Yingxue Pang, Wenjie Wang, Yueying Feng, Luxuan Wang, Yuanyuan Sun, Jun Hao, Fan Li and Song Zhao
Cells 2025, 14(5), 365; https://doi.org/10.3390/cells14050365 - 1 Mar 2025
Viewed by 1133
Abstract
Diabetic kidney disease (DKD) is a prevalent complication associated with diabetes in which podocyte dysfunction significantly contributes to the development and progression of the condition. Ring finger protein 183 (RNF183) is an ER-localized, transmembrane ring finger protein with classical E3 ligase activity. However, [...] Read more.
Diabetic kidney disease (DKD) is a prevalent complication associated with diabetes in which podocyte dysfunction significantly contributes to the development and progression of the condition. Ring finger protein 183 (RNF183) is an ER-localized, transmembrane ring finger protein with classical E3 ligase activity. However, whether RNF183 is involved in glomerular podocyte dysfunction, which is the mechanism of action of DKD, is still poorly understood. In this study, we first demonstrated that RNF183 expression in glomerular podocytes of patients with DKD decreased as the disease progressed. Additionally, our transcriptome sequencing analysis of kidney tissues from diabetic mice revealed a significant reduction in RNF183 expression within the kidney cortex. Similarly, the expression of RNF183 was significantly reduced both in the kidneys of diabetic mice and in human podocytes exposed to high glucose conditions. The downregulation of RNF183 resulted in a suppression of autophagic activity, an increase in apoptotic cell death, and reduced expression of cellular markers in HPC cells. We found that RNF183 was modified via N6-methyladenosine (m6A) RNA methylation. Meanwhile, treatment with meclofenamic acid 2 (MA2), an m6A demethylase inhibitor, resulted in the upregulation of RNF183 expression in HPC cells cultured in high glucose conditions. Furthermore, high glucose treatment decreased the transcription and protein levels in both the m6A writer methyltransferaselike3 (METTL3) and the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). IGF2BP2 assisted with METTL3, which is jointly involved in the transcription of RNF183. Furthermore, we confirmed that RNF183 directly ubiquitinates M2 pyruvate kinase (PKM2) through co-immunoprecipitation (Co-IP) and liquid chromatography–mass spectrometry (LC-MS) experiments. The level of PKM2 ubiquitination was increased following RNF183 overexpression, leading to enhanced PKM2 protein degradation and subsequently alleviating high glucose-induced podocyte damage. The results of this study indicated that RNF183 was regulated via m6A methylation modification and that RNF183 expression was reduced in HPC cells treated with high glucose, which resulted in decreased PKM2 ubiquitination levels and subsequently aggravated podocyte injury. The findings suggest that RNF183 may serve as a potential therapeutic target for diabetic kidney injury, offering new insights into its role in the progression of DKD. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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16 pages, 3146 KiB  
Article
Ubiquitin Ligase Nrdp1 Controls Autophagy-Associated Acrosome Biogenesis and Mitochondrial Arrangement during Spermiogenesis
by Zi-Yu Luo, Tian-Xia Jiang, Tao Zhang, Ping Xu and Xiao-Bo Qiu
Cells 2023, 12(18), 2211; https://doi.org/10.3390/cells12182211 - 5 Sep 2023
Cited by 3 | Viewed by 2153
Abstract
Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes ubiquitination of the mitophagy-associated Parkin and interacts with the pro-autophagic protein SIP/CacyBP. Here, we report that global deletion of Nrdp1 leads to [...] Read more.
Autophagy is critical to acrosome biogenesis and mitochondrial quality control, but the underlying mechanisms remain unclear. The ubiquitin ligase Nrdp1/RNF41 promotes ubiquitination of the mitophagy-associated Parkin and interacts with the pro-autophagic protein SIP/CacyBP. Here, we report that global deletion of Nrdp1 leads to formation of the round-headed sperm and male infertility by disrupting autophagy. Quantitative proteome analyses demonstrated that the expression of many proteins associated with mitochondria, lysosomes, and acrosomes was dysregulated in either spermatids or sperm of the Nrdp1-deficient mice. Deletion of Nrdp1 increased the levels of Parkin but decreased the levels of SIP, the mitochondrial fission protein Drp1 and the mitochondrial protein Tim23 in sperm, accompanied by the inhibition of autophagy, the impairment of acrosome biogenesis and the disruption of mitochondrial arrangement in sperm. Thus, our results uncover an essential role of Nrdp1 in spermiogenesis and male fertility by promoting autophagy, providing important clues to cope with the related male reproductive diseases. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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Review

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28 pages, 1434 KiB  
Review
Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation
by Jessica Jeong, Muhammad Usman, Yitong Li, Xiao Zhen Zhou and Kun Ping Lu
Cells 2024, 13(9), 731; https://doi.org/10.3390/cells13090731 - 23 Apr 2024
Cited by 4 | Viewed by 2875
Abstract
The unique prolyl isomerase Pin1 binds to and catalyzes cis–trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate [...] Read more.
The unique prolyl isomerase Pin1 binds to and catalyzes cis–trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin–proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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22 pages, 1794 KiB  
Review
The Post-Translational Role of UFMylation in Physiology and Disease
by Xingde Wang, Xingzhi Xu and Zhifeng Wang
Cells 2023, 12(21), 2543; https://doi.org/10.3390/cells12212543 - 29 Oct 2023
Cited by 10 | Viewed by 4102
Abstract
Ubiquitin-fold modifier 1 (UFM1) is a newly identified ubiquitin-like protein that has been conserved during the evolution of multicellular organisms. In a similar manner to ubiquitin, UFM1 can become covalently linked to the lysine residue of a substrate via a dedicated enzymatic cascade. [...] Read more.
Ubiquitin-fold modifier 1 (UFM1) is a newly identified ubiquitin-like protein that has been conserved during the evolution of multicellular organisms. In a similar manner to ubiquitin, UFM1 can become covalently linked to the lysine residue of a substrate via a dedicated enzymatic cascade. Although a limited number of substrates have been identified so far, UFM1 modification (UFMylation) has been demonstrated to play a vital role in a variety of cellular activities, including mammalian development, ribosome biogenesis, the DNA damage response, endoplasmic reticulum stress responses, immune responses, and tumorigenesis. In this review, we summarize what is known about the UFM1 enzymatic cascade and its biological functions, and discuss its recently identified substrates. We also explore the pathological role of UFMylation in human disease and the corresponding potential therapeutic targets and strategies. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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14 pages, 1088 KiB  
Review
Emerging Roles of Ubiquitination in Biomolecular Condensates
by Peigang Liang, Jiaqi Zhang and Bo Wang
Cells 2023, 12(18), 2329; https://doi.org/10.3390/cells12182329 - 21 Sep 2023
Cited by 4 | Viewed by 2679
Abstract
Biomolecular condensates are dynamic non-membrane-bound macromolecular high-order assemblies that participate in a growing list of cellular processes, such as transcription, the cell cycle, etc. Disturbed dynamics of biomolecular condensates are associated with many diseases, including cancer and neurodegeneration. Extensive efforts have been devoted [...] Read more.
Biomolecular condensates are dynamic non-membrane-bound macromolecular high-order assemblies that participate in a growing list of cellular processes, such as transcription, the cell cycle, etc. Disturbed dynamics of biomolecular condensates are associated with many diseases, including cancer and neurodegeneration. Extensive efforts have been devoted to uncovering the molecular and biochemical grammar governing the dynamics of biomolecular condensates and establishing the critical roles of protein posttranslational modifications (PTMs) in this process. Here, we summarize the regulatory roles of ubiquitination (a major form of cellular PTM) in the dynamics of biomolecular condensates. We propose that these regulatory mechanisms can be harnessed to combat many diseases. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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21 pages, 1906 KiB  
Review
Ubiquitin Engineering for Interrogating the Ubiquitin–Proteasome System and Novel Therapeutic Strategies
by Jason Q. Tang, Mary M. Marchand and Gianluca Veggiani
Cells 2023, 12(16), 2117; https://doi.org/10.3390/cells12162117 - 21 Aug 2023
Cited by 5 | Viewed by 2843
Abstract
Protein turnover, a highly regulated process governed by the ubiquitin–proteasome system (UPS), is essential for maintaining cellular homeostasis. Dysregulation of the UPS has been implicated in various diseases, including viral infections and cancer, making the proteins in the UPS attractive targets for therapeutic [...] Read more.
Protein turnover, a highly regulated process governed by the ubiquitin–proteasome system (UPS), is essential for maintaining cellular homeostasis. Dysregulation of the UPS has been implicated in various diseases, including viral infections and cancer, making the proteins in the UPS attractive targets for therapeutic intervention. However, the functional and structural redundancies of UPS enzymes present challenges in identifying precise drug targets and achieving target selectivity. Consequently, only 26S proteasome inhibitors have successfully advanced to clinical use thus far. To overcome these obstacles, engineered peptides and proteins, particularly engineered ubiquitin, have emerged as promising alternatives. In this review, we examine the impact of engineered ubiquitin on UPS and non-UPS proteins, as well as on viral enzymes. Furthermore, we explore their potential to guide the development of small molecules targeting novel surfaces, thereby expanding the range of druggable targets. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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16 pages, 25354 KiB  
Review
The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates
by Jiahuan Zheng, Chunxu Chen, Chunqing Guo, Cody Caba, Yufeng Tong and Hengbin Wang
Cells 2023, 12(6), 886; https://doi.org/10.3390/cells12060886 - 13 Mar 2023
Cited by 5 | Viewed by 3405
Abstract
Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a [...] Read more.
Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases. Full article
(This article belongs to the Special Issue Advances in Ubiquitination and Deubiquitination Research)
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