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Cells
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Role of Ubiquitin in Cellular Quality Control
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Role of Ubiquitin in Cellular Quality Control

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

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 24337

Special Issue Editor

Dr. Kwon-Yul Ryu

E-Mail Website
Guest Editor
Department of Life Science, University of Seoul, Seoul 02504, Korea
Interests: ubiquitin; polyubiquitin gene; protein degradation; autophagy; oxidative stress; neurodegenerative disease

Special Issue Information

Dear Colleagues,

Under cellular stress conditions, proteins can be damaged or misfolded; they then must be degraded by the proteasome in a timely manner, otherwise they may accumulate inside cells as toxic protein aggregates. Ubiquitin is a highly conserved eukaryotic protein with various roles inside the cell. Among these roles, targeting misfolded proteins to the proteasome prior to aggregation is essential for cellular survival. When protein aggregates are generated, they can be degraded by autophagy, which is another cellular quality control system. Ubiquitin also plays an essential role in the recognition of protein aggregates by autophagic machinery. Therefore, ubiquitin is required throughout these cellular quality control processes under proteotoxic stress conditions.

Cellular ubiquitin pools are composed of free ubiquitin and ubiquitin conjugates that are in dynamic equilibrium. Cells must maintain free ubiquitin above certain threshold levels, which can fluctuate depending on the cellular environment. As one can imagine, cells need sufficient free ubiquitin to be readily available under stress conditions. In this Special Issue, we would like to focus on the role of ubiquitin in cellular quality control under stress conditions. Cellular effects of ubiquitin can be investigated through alterations in free ubiquitin levels, equilibrium shifts to different forms of ubiquitin, expression of mutant ubiquitin, or regulation of ubiquitin gene expression. Cellular quality control can be monitored by observing the status of protein degradation and protein aggregation, or the activity of the cellular quality control system, such as the ubiquitin–proteasome system or the autophagic pathway. Identifying new roles for ubiquitin or re-examining its role in cellular quality control will provide strong evidence that ubiquitin is a key molecule for cellular survival.

Dr. Kwon-Yul Ryu
Guest Editor

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

  • ubiquitin
  • free ubiquitin
  • ubiquitin gene
  • cellular stress
  • protein degradation
  • protein aggregation
  • cellular survival
  • ubiquitin–proteasome system
  • autophagy

Published Papers (6 papers)

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Research

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14 pages, 5119 KiB  
Article
Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation
by Ji Yeon Lee, Eun-Koung An, Juyoung Hwang, Jun-O. Jin and Peter C. W. Lee
Cells 2022, 11(1), 105; https://doi.org/10.3390/cells11010105 - 29 Dec 2021
Cited by 10 | Viewed by 2006
Abstract
Ubiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin-activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were elevated [...] Read more.
Ubiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin-activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were elevated in T cells by toll-like receptor agonists and anti-CD3/28 antibody stimulation, but not in dendritic cells, macrophages, B cells, and natural killer cells. Additionally, we generated T cell-specific UBA6-deficient mice and found that UBA6-deficient CD4 and CD8 T cells elevated the production of interferon-gamma (IFN-γ). Moreover, the transfer of UBA6-deficient CD4 and CD8 T cells in RAG1-knockout mice exacerbated the development of multi-organ inflammation compared with control CD4 and CD8 T cell transfer. In human peripheral blood CD4 and CD8 T cells, basal levels of UBA6 in lupus patients presented much lower than those in healthy controls. Moreover, the IFN-γ production efficiency of CD4 and CD8 T cells was negatively correlated to UBA6 levels in patients with lupus. Finally, we found that the function of UBA6 was mediated by destabilization of IκBα degradation, thereby increasing NF-κB p65 activation in the T cells. Our study identifies UBA6 as a critical regulator of IFN-γ production in T cells by modulating the NF-κB p65 activation pathway. Full article
(This article belongs to the Special Issue Role of Ubiquitin in Cellular Quality Control)
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23 pages, 7388 KiB  
Article
RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association
by Valérie C. Cabana, Antoine Y. Bouchard, Audrey M. Sénécal, Kim Ghilarducci, Saïd Kourrich, Laurent Cappadocia and Marc P. Lussier
Cells 2021, 10(11), 3063; https://doi.org/10.3390/cells10113063 - 06 Nov 2021
Cited by 3 | Viewed by 3202
Abstract
Developmental and epileptic encephalopathies (DEE) are rare and serious neurological disorders characterized by severe epilepsy with refractory seizures and a significant developmental delay. Recently, DEE73 was linked to genetic alterations of the RNF13 gene, which convert positions 311 or 312 in the RNF13 [...] Read more.
Developmental and epileptic encephalopathies (DEE) are rare and serious neurological disorders characterized by severe epilepsy with refractory seizures and a significant developmental delay. Recently, DEE73 was linked to genetic alterations of the RNF13 gene, which convert positions 311 or 312 in the RNF13 protein from leucine to serine or proline, respectively (L311S and L312P). Using a fluorescence microscopy approach to investigate the molecular and cellular mechanisms affected by RNF13 protein variants, the current study shows that wild-type RNF13 localizes extensively with endosomes and lysosomes, while L311S and L312P do not extensively colocalize with the lysosomal marker Lamp1. Our results show that RNF13 L311S and L312P proteins affect the size of endosomal vesicles along with the temporal and spatial progression of fluorescently labeled epidermal growth factor, but not transferrin, in the endolysosomal system. Furthermore, GST-pulldown and co-immunoprecipitation show that RNF13 variants disrupt association with AP-3 complex. Knockdown of AP-3 complex subunit AP3D1 alters the lysosomal localization of wild-type RNF13 and similarly affects the size of endosomal vesicles. Importantly, our study provides a first step toward understanding the cellular and molecular mechanism altered by DEE73-associated genetic variations of RNF13. Full article
(This article belongs to the Special Issue Role of Ubiquitin in Cellular Quality Control)
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13 pages, 1922 KiB  
Article
Formation of Non-Nucleoplasmic Proteasome Foci during the Late Stage of Hyperosmotic Stress
by Jeeyoung Lee, Ly Thi Huong Luu Le, Eunkyoung Kim and Min Jae Lee
Cells 2021, 10(9), 2493; https://doi.org/10.3390/cells10092493 - 21 Sep 2021
Cited by 6 | Viewed by 2648
Abstract
Cellular stress induces the formation of membraneless protein condensates in both the nucleus and cytoplasm. The nucleocytoplasmic transport of proteins mainly occurs through nuclear pore complexes (NPCs), whose efficiency is affected by various stress conditions. Here, we report that hyperosmotic stress compartmentalizes nuclear [...] Read more.
Cellular stress induces the formation of membraneless protein condensates in both the nucleus and cytoplasm. The nucleocytoplasmic transport of proteins mainly occurs through nuclear pore complexes (NPCs), whose efficiency is affected by various stress conditions. Here, we report that hyperosmotic stress compartmentalizes nuclear 26S proteasomes into dense nuclear foci, independent of signaling cascades. Most of the proteasome foci were detected between the condensed chromatin mass and inner nuclear membrane. The proteasome-positive puncta were not colocalized with other types of nuclear bodies and were reversibly dispersed when cells were returned to the isotonic medium. The structural integrity of 26S proteasomes in the nucleus was slightly affected under the hyperosmotic condition. We also found that these insulator-body-like proteasome foci were possibly formed through disrupted nucleus-to-cytosol transport, which was mediated by the sequestration of NPC components into osmostress-responding stress granules. These data suggest that phase separation in both the nucleus and cytosol may be a major cell survival mechanism during hyperosmotic stress conditions. Full article
(This article belongs to the Special Issue Role of Ubiquitin in Cellular Quality Control)
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Review

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17 pages, 1114 KiB  
Review
Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress
by Yanan Li, Shujing Li and Huijian Wu
Cells 2022, 11(5), 851; https://doi.org/10.3390/cells11050851 - 01 Mar 2022
Cited by 60 | Viewed by 7870
Abstract
In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the [...] Read more.
In response to environmental stimuli, cells make a series of adaptive changes to combat the injury, repair the damage, and increase the tolerance to the stress. However, once the damage is too serious to repair, the cells will undergo apoptosis to protect the overall cells through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions to form protein aggregation, which may ultimately produce serious damage to the cells. Ubiquitin plays an important role in the degradation of these unnatural proteins by tagging with ubiquitin chains in the ubiquitin–proteasome or autophagy system. If the two processes fail to eliminate the abnormal protein aggregates, the cells will move to apoptosis and death. Dysregulation of ubiquitin–proteasome system (UPS) and autophagy may result in the development of numerous diseases. This review focuses on the molecular mechanisms of UPS and autophagy in clearance of intracellular protein aggregates, and the relationship between dysregulation of ubiquitin network and diseases. Full article
(This article belongs to the Special Issue Role of Ubiquitin in Cellular Quality Control)
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22 pages, 1685 KiB  
Review
From Drosophila to Human: Biological Function of E3 Ligase Godzilla and Its Role in Disease
by Valérie C. Cabana and Marc P. Lussier
Cells 2022, 11(3), 380; https://doi.org/10.3390/cells11030380 - 23 Jan 2022
Cited by 3 | Viewed by 3380
Abstract
The ubiquitin–proteasome system is of fundamental importance in all fields of biology due to its impact on proteostasis and in regulating cellular processes. Ubiquitination, a type of protein post-translational modification, involves complex enzymatic machinery, such as E3 ubiquitin ligases. The E3 ligases regulate [...] Read more.
The ubiquitin–proteasome system is of fundamental importance in all fields of biology due to its impact on proteostasis and in regulating cellular processes. Ubiquitination, a type of protein post-translational modification, involves complex enzymatic machinery, such as E3 ubiquitin ligases. The E3 ligases regulate the covalent attachment of ubiquitin to a target protein and are involved in various cellular mechanisms, including the cell cycle, cell division, endoplasmic reticulum stress, and neurotransmission. Because the E3 ligases regulate so many physiological events, they are also associated with pathologic conditions, such as cancer, neurological disorders, and immune-related diseases. This review focuses specifically on the protease-associated transmembrane-containing the Really Interesting New Gene (RING) subset of E3 ligases. We describe the structure, partners, and physiological functions of the Drosophila Godzilla E3 ligase and its human homologues, RNF13, RNF167, and ZNRF4. Also, we summarize the information that has emerged during the last decade regarding the association of these E3 ligases with pathophysiological conditions, such as cancer, asthma, and rare genetic disorders. We conclude by highlighting the limitations of the current knowledge and pinpointing the unresolved questions relevant to RNF13, RNF167, and ZNRF4 ubiquitin ligases. Full article
(This article belongs to the Special Issue Role of Ubiquitin in Cellular Quality Control)
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16 pages, 1054 KiB  
Review
Ubiquitin-Conjugating Enzymes in Cancer
by Quyen Thu Bui, Jeong Hee Hong, Minseok Kwak, Ji Yeon Lee and Peter Chang-Whan Lee
Cells 2021, 10(6), 1383; https://doi.org/10.3390/cells10061383 - 04 Jun 2021
Cited by 21 | Viewed by 4257
Abstract
The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 [...] Read more.
The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies. Full article
(This article belongs to the Special Issue Role of Ubiquitin in Cellular Quality Control)
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