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Ubiquitination in Health and Diseases: Volume II

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 23591

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Special Issue Editor

Dr. Tomoaki Ishigami

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Guest Editor

Department of Medical Science and Cardio-Renal Medicine, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama, Japan
Interests: hypertension; salt sensitivity; tubular transport; epithelial sodium channels; ubiquitination; Nedd4-2 and atherosclerosis
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Special Issue Information

Dear Colleagues,

Ubiquitination is a representative, reversible biological process for the post-translational modification of various proteins with multiple catalytic sequences, including ubiquitin itself, the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes, and the E3 ubiquitin ligase and deubiquitinating enzymes. Since the ubiquitin–proteasome system plays a pivotal role in various molecular life phenomenon, such as cell cycle control, protein quality control, and cell surface expression of ion transporters, its failure causes various diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and hypertension. Actually, various genetic diseases derived from abnormalities in genes involved in ubiquitination have been reported, such as Parkinsonism, Cushing disease, and Liddle syndrome. Ubiquitination is a post-translational modification of proteins subsequent to phosphorylation, and approximately 40% of the proteins encoded by human genes undergo this modification. Although clinical applications targeting ubiquitination are still limited compared with those directed to kinase systems such as tyrosin kinases, for which an inventory of tyrosine kinase inhibitors is already available in clinical settings, many compounds affecting ubiquitination and presenting high pharmacological activity have been identified at the basic research level; therefore, future developments can be expected. Abnormalities of E3 ubiquitin ligase affect the phenotypes specific to each target substrate, which, thus, are also attractive targets for selective drug discovery. In this Special Issue of the International Journal of Molecular Science, we would like to invite your contributions in the form of either original research articles or reviews, which addresses the expanding field of mechanic, functional and pharmacological dissections about the physiological and pathological implications of specific ubiquitination reactions.

Dr. Tomoaki Ishigami
Guest Editor

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Keywords

ubiquitination
E1 ubiquitin-activating enzyme
E2 ubiquitin-conjugating enzyme
E3 ubiquitin ligase
Deubiquitinating enzyme
Ubiqutin-proteasome system
Drug discovery

Published Papers (5 papers)

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Research

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13 pages, 555 KiB

Open AccessArticle

Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System

by Alyssa Tidmore, Sucharita M. Dutta, Arriyam S. Fesshaye, William K. Russell, Vania D. Duncan and Richard A. Britten

Int. J. Mol. Sci. 2021, 22(14), 7713; https://doi.org/10.3390/ijms22147713 - 19 Jul 2021

Cited by 4 | Viewed by 2156

Abstract

Exposure of rodents to <20 cGy Space Radiation (SR) impairs performance in several hippocampus-dependent cognitive tasks, including spatial memory. However, there is considerable inter-individual susceptibility to develop SR-induced spatial memory impairment. In this study, a robust label-free mass spectrometry (MS)-based unbiased proteomic profiling approach was used to characterize the composition of the hippocampal proteome in adult male Wistar rats exposed to 15 cGy of 1 GeV/n ⁴⁸Ti and their sham counterparts. Unique protein signatures were identified in the hippocampal proteome of: (1) sham rats, (2) Ti-exposed rats, (3) Ti-exposed rats that had sham-like spatial memory performance, and (4) Ti-exposed rats that impaired spatial memory performance. Approximately 14% (159) of the proteins detected in hippocampal proteome of sham rats were not detected in the Ti-exposed rats. We explored the possibility that the loss of the Sham-only proteins may arise as a result of SR-induced changes in protein homeostasis. SR-exposure was associated with a switch towards increased pro-ubiquitination proteins from that seen in Sham. These data suggest that the role of the ubiquitin-proteome system as a determinant of SR-induced neurocognitive deficits needs to be more thoroughly investigated. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases: Volume II)

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15 pages, 3454 KiB

Open AccessArticle

The Role of Autophagy in Chemical Proteasome Inhibition Model of Retinal Degeneration

by Merry Gunawan, Choonbing Low, Kurt Neo, Siawey Yeo, Candice Ho, Veluchamy A. Barathi, Anita Sookyee Chan, Najam A. Sharif and Masaaki Kageyama

Int. J. Mol. Sci. 2021, 22(14), 7271; https://doi.org/10.3390/ijms22147271 - 6 Jul 2021

Cited by 4 | Viewed by 2147

Abstract

We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin–proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases: Volume II)

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Review

Jump to: Research

23 pages, 22531 KiB

Open AccessReview

The Next Frontier: Translational Development of Ubiquitination, SUMOylation, and NEDDylation in Cancer

by Nicole E. Pellegrino, Arcan Guven, Kayleigh Gray, Punit Shah, Gargi Kasture, Maria-Dorothea Nastke, Anjan Thakurta, Stephane Gesta, Vivek K. Vishnudas, Niven R. Narain and Michael A. Kiebish

Int. J. Mol. Sci. 2022, 23(7), 3480; https://doi.org/10.3390/ijms23073480 - 23 Mar 2022

Cited by 19 | Viewed by 4314

Abstract

Post-translational modifications of proteins ensure optimized cellular processes, including proteostasis, regulated signaling, cell survival, and stress adaptation to maintain a balanced homeostatic state. Abnormal post-translational modifications are associated with cellular dysfunction and the occurrence of life-threatening diseases, such as cancer and neurodegenerative diseases. Therefore, some of the frequently seen protein modifications have been used as disease markers, while others are targeted for developing specific therapies. The ubiquitin and ubiquitin-like post-translational modifiers, namely, small ubiquitin-like modifier (SUMO) and neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8), share several features, such as protein structures, enzymatic cascades mediating the conjugation process, and targeted amino acid residues. Alterations in the regulatory mechanisms lead to aberrations in biological processes during tumorigenesis, including the regulation of tumor metabolism, immunological modulation of the tumor microenvironment, and cancer stem cell stemness, besides many more. Novel insights into ubiquitin and ubiquitin-like pathways involved in cancer biology reveal a potential interplay between ubiquitination, SUMOylation, and NEDDylation. This review outlines the current understandings of the regulatory mechanisms and assay capabilities of ubiquitination, SUMOylation, and NEDDylation. It will further highlight the role of ubiquitination, SUMOylation, and NEDDylation in tumorigenesis. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases: Volume II)

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26 pages, 1584 KiB

Open AccessReview

The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease

by Jun Goto, Yoichiro Otaki, Tetsu Watanabe and Masafumi Watanabe

Int. J. Mol. Sci. 2021, 22(11), 6065; https://doi.org/10.3390/ijms22116065 - 4 Jun 2021

Cited by 10 | Viewed by 5004

Abstract

Despite advances in medicine, cardiac disease remains an increasing health problem associated with a high mortality rate. Maladaptive cardiac remodeling, such as cardiac hypertrophy and fibrosis, is a risk factor for heart failure; therefore, it is critical to identify new therapeutic targets. Failing heart is reported to be associated with hyper-ubiquitylation and impairment of the ubiquitin–proteasome system, indicating an importance of ubiquitylation in the development of cardiac disease. Ubiquitylation is a post-translational modification that plays a pivotal role in protein function and degradation. In 1995, homologous to E6AP C-terminus (HECT) type E3 ligases were discovered. E3 ligases are key enzymes in ubiquitylation and are classified into three families: really interesting new genes (RING), HECT, and RING-between-RINGs (RBRs). Moreover, 28 HECT-type E3 ligases have been identified in human beings. It is well conserved in evolution and is characterized by the direct attachment of ubiquitin to substrates. HECT-type E3 ligase is reported to be involved in a wide range of human diseases and health. The role of HECT-type E3 ligases in the development of cardiac diseases has been uncovered in the last decade. There are only a few review articles summarizing recent advancements regarding HECT-type E3 ligase in the field of cardiac disease. This study focused on cardiac remodeling and described the role of HECT-type E3 ligases in the development of cardiac disease. Moreover, this study revealed that the current knowledge could be exploited for the development of new clinical therapies. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases: Volume II)

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29 pages, 5803 KiB

Open AccessReview

Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

by Shiyao Chen, Yunqi Liu and Huchen Zhou

Int. J. Mol. Sci. 2021, 22(9), 4546; https://doi.org/10.3390/ijms22094546 - 27 Apr 2021

Cited by 59 | Viewed by 8685

Abstract

Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases: Volume II)

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