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Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs)
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Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs)

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 7345

Special Issue Editors

Dr. Minsoo Kim

E-Mail Website
Guest Editor
Laboratory of Integrative Molecular Medicine, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
Interests: post translational modification; targeted protein degradation; pathogen
Dr. Tsunehiro Mizushima

E-Mail Website
Guest Editor
Department of Life Science, Graduate School of Science, University of Hyogo, 2167 Shosha, Himeji 671-2280, Japan
Interests: ubiquitin; structural biology; molecular mechanism
Dr. Hideki Yashiroda

E-Mail Website
Guest Editor
Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan
Interests: ubiquitin; proteasome; Saccharomyces cerevisiae

Special Issue Information

Dear Colleagues,

Ubiquitin is a crucial post-translational protein, widely distributed in eukaryotic cells, which dynamically regulates proteins related to various cellular activities, such as signal transduction, cell cycles, inflammatory responses, autophagy, and apoptosis. The ubiquitin–proteasome system (UPS) has an impact on various intracellular processes and substrates. Like most post-translational modifications, the UPS is a reversible process. The dynamic balance of ubiquitination and deubiquitination in cells is the basic guarantee for maintaining normal physiological functions, but its imbalance can lead to many diseases, such as infectious disease, cancer, and neurological disorders. Of these, E3 ubiquitin ligases and deubiquitinases (DUBs) play the most prominent roles in the overall ubiquitination process. E3 ubiquitin ligases control ubiquitination by recognizing specific motifs. Ubiquitin ligase-mediated ubiquitination would be antagonized by DUBs. Therefore, understanding ubiquitination and deubiquitination is an important topic. However, the efficient and selective targeting of ubiquitin-proteasome remains a challenge.

It is worth noting that bacterial effector proteins would also target the host ubiquitin system, often acting as ubiquitin ligases and deubiquitinases. Exploring the diversity and mechanisms of bacterial ubiquitin-modulating enzymes can provide insights into bacterial pathogenesis, broaden our understanding of host ubiquitination pathways, and potentially lead to novel therapeutic strategies.

In this Special Issue of Cells, we would like to invite contributions addressing the roles and underlying mechanisms of ubiquitin ligases (E3) and deubiquitinases, and to offer new insights into this interesting and important research field. Original research papers, review articles, and novel methods that cover these topics or similar topics are welcome.

Dr. Minsoo Kim
Dr. Tsunehiro Mizushima
Dr. Hideki Yashiroda
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. Cells is an international peer-reviewed open access semimonthly 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

  • E3 ubiquitin ligases
  • deubiquitinases
  • ubiquitin
  • ubiquitination
  • proteasome

Published Papers (6 papers)

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Research

Jump to: Review

19 pages, 3914 KiB  
Article
The E3 Ubiquitin Protein Ligase LINCR Amplifies the TLR-Mediated Signals through Direct Degradation of MKP1
by Takumi Yokosawa, Sayoko Miyagawa, Wakana Suzuki, Yuki Nada, Yusuke Hirata, Takuya Noguchi and Atsushi Matsuzawa
Cells 2024, 13(8), 687; https://doi.org/10.3390/cells13080687 - 15 Apr 2024
Viewed by 533
Abstract
Toll-like receptors (TLRs) induce innate immune responses through activation of intracellular signaling pathways, such as MAP kinase and NF-κB signaling pathways, and play an important role in host defense against bacterial or viral infections. Meanwhile, excessive activation of TLR signaling leads to a [...] Read more.
Toll-like receptors (TLRs) induce innate immune responses through activation of intracellular signaling pathways, such as MAP kinase and NF-κB signaling pathways, and play an important role in host defense against bacterial or viral infections. Meanwhile, excessive activation of TLR signaling leads to a variety of inflammatory disorders, including autoimmune diseases. TLR signaling is therefore strictly controlled to balance optimal immune response and inflammation. However, its balancing mechanisms are not fully understood. In this study, we identified the E3 ubiquitin ligase LINCR/ NEURL3 as a critical regulator of TLR signaling. In LINCR-deficient cells, the sustained activation of JNK and p38 MAPKs induced by the agonists for TLR3, TLR4, and TLR5, was clearly attenuated. Consistent with these observations, TLR-induced production of a series of inflammatory cytokines was significantly attenuated, suggesting that LINCR positively regulates innate immune responses by promoting the activation of JNK and p38. Interestingly, our further mechanistic study identified MAPK phosphatase-1 (MKP1), a negative regulator of MAP kinases, as a ubiquitination target of LINCR. Thus, our results demonstrate that TLRs fine-tune the activation of MAP kinase pathways by balancing LINCR (the positive regulator) and MKP1 (the negative regulator), which may contribute to the induction of optimal immune responses. Full article
(This article belongs to the Special Issue Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs))
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19 pages, 3690 KiB  
Article
UBE3C Facilitates the ER-Associated and Peripheral Degradation of Misfolded CFTR
by Yuka Kamada, Hazuki Tateishi, Uta Nakayamada, Daichi Hinata, Ayuka Iwasaki, Jingxin Zhu, Ryosuke Fukuda and Tsukasa Okiyoneda
Cells 2023, 12(23), 2741; https://doi.org/10.3390/cells12232741 - 30 Nov 2023
Cited by 1 | Viewed by 1070
Abstract
The ubiquitin E3 ligase UBE3C promotes the proteasomal degradation of cytosolic proteins and endoplasmic reticulum (ER) membrane proteins. UBE3C is proposed to function downstream of the RNF185/MBRL ER-associated degradation (ERAD) branch, contributing to the ERAD of select membrane proteins. Here, we report that [...] Read more.
The ubiquitin E3 ligase UBE3C promotes the proteasomal degradation of cytosolic proteins and endoplasmic reticulum (ER) membrane proteins. UBE3C is proposed to function downstream of the RNF185/MBRL ER-associated degradation (ERAD) branch, contributing to the ERAD of select membrane proteins. Here, we report that UBE3C facilitates the ERAD of misfolded CFTR, even in the absence of both RNF185 and its functional ortholog RNF5 (RNF5/185). Unlike RNF5/185, UBE3C had a limited impact on the ubiquitination of misfolded CFTR. UBE3C knockdown (KD) resulted in an additional increase in the functional ∆F508-CFTR channels on the plasma membrane when combined with the RNF5/185 ablation, particularly in the presence of clinically used CFTR modulators. Interestingly, although UBE3C KD failed to attenuate the ERAD of insig-1, it reduced the ERAD of misfolded ∆Y490-ABCB1 and increased cell surface expression. UBE3C KD also stabilized the mature form of ∆F508-CFTR and increased the cell surface level of T70-CFTR, a class VI CFTR mutant. These results suggest that UBE3C plays a vital role in the ERAD of misfolded CFTR and ABCB1, even within the RNF5/185-independent ERAD pathway, and it may also be involved in maintaining the peripheral quality control of CFTR. Full article
(This article belongs to the Special Issue Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs))
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Review

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30 pages, 10423 KiB  
Review
Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond
by Aggie Lawer, Luke Schulz, Renata Sawyer and Xuyu Liu
Cells 2024, 13(5), 426; https://doi.org/10.3390/cells13050426 - 28 Feb 2024
Viewed by 1128
Abstract
Post-translational modifications (PTMs) are crucial mechanisms that underlie the intricacies of biological systems and disease mechanisms. This review focuses on the latest advancements in the design of heterobifunctional small molecules that hijack PTM machineries for target-specific modifications in living systems. A key innovation [...] Read more.
Post-translational modifications (PTMs) are crucial mechanisms that underlie the intricacies of biological systems and disease mechanisms. This review focuses on the latest advancements in the design of heterobifunctional small molecules that hijack PTM machineries for target-specific modifications in living systems. A key innovation in this field is the development of proteolysis-targeting chimeras (PROTACs), which promote the ubiquitination of target proteins for proteasomal degradation. The past decade has seen several adaptations of the PROTAC concept to facilitate targeted (de)phosphorylation and acetylation. Protein fusion tags have been particularly vital in these proof-of-concept studies, aiding in the investigation of the functional roles of post-translationally modified proteins linked to diseases. This overview delves into protein-tagging strategies that enable the targeted modulation of ubiquitination, phosphorylation, and acetylation, emphasizing the synergies and challenges of integrating heterobifunctional molecules with protein tags in PTM research. Despite significant progress, many PTMs remain to be explored, and protein tag-assisted PTM-inducing chimeras will continue to play an important role in understanding the fundamental roles of protein PTMs and in exploring the therapeutic potential of manipulating protein modifications, particularly for targets not yet addressed by existing drugs. Full article
(This article belongs to the Special Issue Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs))
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10 pages, 785 KiB  
Review
E3 Ligases Regulate Organelle Inheritance in Yeast
by Keisuke Obara, Kohei Nishimura and Takumi Kamura
Cells 2024, 13(4), 292; https://doi.org/10.3390/cells13040292 - 06 Feb 2024
Viewed by 836
Abstract
Saccharomyces cerevisiae proliferates by budding, which includes the formation of a cytoplasmic protrusion called the ‘bud’, into which DNA, RNA, proteins, organelles, and other materials are transported. The transport of organelles into the growing bud must be strictly regulated for the proper inheritance [...] Read more.
Saccharomyces cerevisiae proliferates by budding, which includes the formation of a cytoplasmic protrusion called the ‘bud’, into which DNA, RNA, proteins, organelles, and other materials are transported. The transport of organelles into the growing bud must be strictly regulated for the proper inheritance of organelles by daughter cells. In yeast, the RING-type E3 ubiquitin ligases, Dma1 and Dma2, are involved in the proper inheritance of mitochondria, vacuoles, and presumably peroxisomes. These organelles are transported along actin filaments toward the tip of the growing bud by the myosin motor protein, Myo2. During organelle transport, organelle-specific adaptor proteins, namely Mmr1, Vac17, and Inp2 for mitochondria, vacuoles, and peroxisomes, respectively, bridge the organelles and myosin. After reaching the bud, the adaptor proteins are ubiquitinated by the E3 ubiquitin ligases and degraded by the proteasome. Targeted degradation of the adaptor proteins is necessary to unload vacuoles, mitochondria, and peroxisomes from the actin–myosin machinery. Impairment of the ubiquitination of adaptor proteins results in the failure of organelle release from myosin, which, in turn, leads to abnormal dynamics, morphology, and function of the inherited organelles, indicating the significance of proper organelle unloading from myosin. Herein, we summarize the role and regulation of E3 ubiquitin ligases during organelle inheritance in yeast. Full article
(This article belongs to the Special Issue Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs))
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Graphical abstract

12 pages, 748 KiB  
Review
Targeted Protein Degradation Systems: Controlling Protein Stability Using E3 Ubiquitin Ligases in Eukaryotic Species
by Yoshitaka Ogawa, Taisei P. Ueda, Keisuke Obara, Kohei Nishimura and Takumi Kamura
Cells 2024, 13(2), 175; https://doi.org/10.3390/cells13020175 - 17 Jan 2024
Viewed by 1348
Abstract
This review explores various methods for modulating protein stability to achieve target protein degradation, which is a crucial aspect in the study of biological processes and drug design. Thirty years have passed since the introduction of heat-inducible degron cells utilizing the N-end rule, [...] Read more.
This review explores various methods for modulating protein stability to achieve target protein degradation, which is a crucial aspect in the study of biological processes and drug design. Thirty years have passed since the introduction of heat-inducible degron cells utilizing the N-end rule, and methods for controlling protein stability using the ubiquitin–proteasome system have moved from academia to industry. This review covers protein stability control methods, from the early days to recent advancements, and discusses the evolution of techniques in this field. This review also addresses the challenges and future directions of protein stability control techniques by tracing their development from the inception of protein stability control methods to the present day. Full article
(This article belongs to the Special Issue Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs))
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19 pages, 2871 KiB  
Review
Role of Ubiquitination and Epigenetics in the Regulation of AhR Signaling in Carcinogenesis and Metastasis: “Albatross around the Neck” or “Blessing in Disguise”
by Ammad Ahmad Farooqi, Venera Rakhmetova, Gulnara Kapanova, Gulnur Tanbayeva, Akmaral Mussakhanova, Akmaral Abdykulova and Alma-Gul Ryskulova
Cells 2023, 12(19), 2382; https://doi.org/10.3390/cells12192382 - 29 Sep 2023
Cited by 1 | Viewed by 1526
Abstract
The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. [...] Read more.
The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. AhR mediates transcriptional programming in a ligand-specific, context-specific and cell-type-specific manner. Pioneering cutting-edge research works have provided fascinating new insights into the mechanistic role of AhR-driven downstream signaling in a wide variety of cancers. AhR ligands derived from food, environmental contaminants and intestinal microbiota strategically activated AhR signaling and regulated multiple stages of cancer. Although AhR has classically been viewed and characterized as a ligand-regulated transcriptional factor, its role as a ubiquitin ligase is fascinating. Accordingly, recent evidence has paradigmatically shifted our understanding and urged researchers to drill down deep into these novel and clinically valuable facets of AhR biology. Our rapidly increasing realization related to AhR-mediated regulation of the ubiquitination and proteasomal degradation of different proteins has started to scratch the surface of intriguing mechanisms. Furthermore, AhR and epigenome dynamics have shown previously unprecedented complexity during multiple stages of cancer progression. AhR not only transcriptionally regulated epigenetic-associated molecules, but also worked with epigenetic-modifying enzymes during cancer progression. In this review, we have summarized the findings obtained not only from cell-culture studies, but also from animal models. Different clinical trials are currently being conducted using AhR inhibitors and PD-1 inhibitors (Pembrolizumab and nivolumab), which confirm the linchpin role of AhR-related mechanistic details in cancer progression. Therefore, further studies are required to develop a better comprehension of the many-sided and “diametrically opposed” roles of AhR in the regulation of carcinogenesis and metastatic spread of cancer cells to the secondary organs. Full article
(This article belongs to the Special Issue Roles and Mechanisms of Ubiquitin Ligases (E3) and Deubiquitinases (DUBs))
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Structural dynamics analysis on the USP14 activation by AKT-mediated phosphorylation
Authors: Raju Dash; Non-Nuoc Tran; Sung Bae Lee; Byung-Hoon Lee
Affiliation: Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
Abstract: Ubiquitin-specific protease 14 (USP14), one of the three major proteasome-associated deubiqui-tinating enzymes (DUBs), is known to be activated by the AKT-mediated phosphorylation at Ser432. Thereby, AKT can regulate global protein degradation by controlling the ubiquitin-proteasome system (UPS). However, the exact molecular mechanism of USP14 activation by AKT phosphorylation at the atomic level remains unknown. By performing the molecular dynamics (MD) simulation of the USP14 catalytic domain at three different states (inactive, active, and USP14-ubiquitin complex), we characterized the change of structural dynamics by phosphoryla-tion. We observed that the Ser432 phosphorylation induced substantial conformational changes of USP14 in the blocking loop (BL) region to fold it from an open loop into a β-sheet, which is critical for USP14 activation. Furthermore, phosphorylation also increased the frequency of criti-cal hydrogen bonding and salt bridge interactions between USP14 and ubiquitin, which is essen-tial for DUB activity. Structural dynamics insights from this study pinpoint the important local conformational landscape of USP14 by the phosphorylation event, which would be critical for understanding USP14-mediated proteasome regulation and designing future therapeutics.

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