Ubiquitination in Health and Disease

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

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 65630

Special Issue Editors

Department of Life Sciences, University of Trieste, Via L. Giorgieri, 5, 34127 Trieste, Italy
Interests: genetic diseases; TRIM E3 ubiquitin ligases; ubiquitination
Special Issues, Collections and Topics in MDPI journals
Department of Molecular Medicine and Medical Biotechnology, University of Naples, Federico II, Via S. Pansini 5, 80131 Naples, Italy
Interests: medical genetics; epigenetics; chromatinopathies; disease discovery; TRIM proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ubiquitination is a post-translational modification process that controls the degradation, signaling and activity of many, if not all, cellular proteins. Ubiquitination needs to be finely tuned and is catalyzed and controlled by several players: ubiquitin; the E1 ubiquitin activating enzyme, the E2 ubiquitin conjugating enzymes, the E3 ubiquitin ligases, which compose the ubiquitination cascade; the deubiquitination enzymes that reverse the modification; and the proteins that recognize the ubiquitination code and translate the signal. Substrates can be modified with a single ubiquitin peptide, in one or multiple sites, or with a poly-ubiquitin chain. The topology of the built ubiquitin chain determines the fate of the targeted substrate. In cells also free poly-ubiquitin chains, which are not conjugated to any target protein, can be synthesized. In recent years, considerable progress has been made in the understanding the molecular action of ubiquitin in signaling pathways and how alterations in the ubiquitin system lead to the development of several human diseases from cancer, metabolic syndromes, neurodegenerative diseases, inflammatory disorders, and rare genetic disorders.

In this Special Issue of Cells, we invite your contributions, either in the form of original research articles or reviews addressing the expanding field of mechanistic and functional insights into the physiological and pathological role of specific ubiquitination pathways and components.

Prof. Germana Meroni
Dr. Giuseppe Merla
Guest Editors

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Keywords

  • ubiquitin
  • E3 ubiquitin ligases
  • proteasome
  • E2 ubiquitin conjugating enzymes
  • ubiquitin binding domains

Published Papers (11 papers)

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Research

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15 pages, 5255 KiB  
Article
Analysis of the Zn-Binding Domains of TRIM32, the E3 Ubiquitin Ligase Mutated in Limb Girdle Muscular Dystrophy 2H
by Elisa Lazzari, Medhat S. El-Halawany, Matteo De March, Floriana Valentino, Francesco Cantatore, Chiara Migliore, Silvia Onesti and Germana Meroni
Cells 2019, 8(3), 254; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8030254 - 16 Mar 2019
Cited by 13 | Viewed by 3922
Abstract
Members of the tripartite motif family of E3 ubiquitin ligases are characterized by the presence of a conserved N-terminal module composed of a RING domain followed by one or two B-box domains, a coiled-coil and a variable C-terminal region. The RING and B-box [...] Read more.
Members of the tripartite motif family of E3 ubiquitin ligases are characterized by the presence of a conserved N-terminal module composed of a RING domain followed by one or two B-box domains, a coiled-coil and a variable C-terminal region. The RING and B-box are both Zn-binding domains but, while the RING is found in a large number of proteins, the B-box is exclusive to the tripartite motif (TRIM) family members in metazoans. Whereas the RING has been extensively characterized and shown to possess intrinsic E3 ligase catalytic activity, much less is known about the role of the B-box domains. In this study, we adopted an in vitro approach using recombinant point- and deletion-mutants to characterize the contribution of the TRIM32 Zn-binding domains to the activity of this E3 ligase that is altered in a genetic form of muscular dystrophy. We found that the RING domain is crucial for E3 ligase activity and E2 specificity, whereas a complete B-box domain is involved in chain assembly rate modulation. Further, in vitro, the RING domain is necessary to modulate TRIM32 oligomerization, whereas, in cells, both the RING and B-box cooperate to specify TRIM32 subcellular localization, which if altered may impact the pathogenesis of diseases. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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19 pages, 3736 KiB  
Article
UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment
by Cécile Polge, Julien Aniort, Andrea Armani, Agnès Claustre, Cécile Coudy-Gandilhon, Clara Tournebize, Christiane Deval, Lydie Combaret, Daniel Béchet, Marco Sandri, Didier Attaix and Daniel Taillandier
Cells 2018, 7(11), 214; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7110214 - 16 Nov 2018
Cited by 6 | Viewed by 3859
Abstract
Skeletal muscle mass is reduced during many diseases or physiological situations (disuse, aging), which results in decreased strength and increased mortality. Muscle mass is mainly controlled by the ubiquitin-proteasome system (UPS), involving hundreds of ubiquitinating enzymes (E2s and E3s) that target their dedicated [...] Read more.
Skeletal muscle mass is reduced during many diseases or physiological situations (disuse, aging), which results in decreased strength and increased mortality. Muscle mass is mainly controlled by the ubiquitin-proteasome system (UPS), involving hundreds of ubiquitinating enzymes (E2s and E3s) that target their dedicated substrates for subsequent degradation. We recently demonstrated that MuRF1, an E3 ubiquitin ligase known to bind to sarcomeric proteins (telethonin, α-actin, myosins) during catabolic situations, interacts with 5 different E2 enzymes and that these E2-MuRF1 couples are able to target telethonin, a small sarcomeric protein, for degradation. Amongst the E2s interacting with MuRF1, E2E1 was peculiar as the presence of the substrate was necessary for optimal MuRF1-E2E1 interaction. In this work, we focused on the putative role of E2E1 during skeletal muscle atrophy. We found that E2E1 expression was restricted to type I and type IIA muscle fibers and was not detectable in type IIB fibers. This strongly suggests that E2E1 targets are fiber-specific and may be strongly linked to the contractile and metabolic properties of the skeletal muscle. However, E2E1 knockdown was not sufficient for preserving the protein content in C2C12 myotubes subjected to a catabolic state (dexamethasone treatment), suggesting that E2E1 is not involved in the development of muscle atrophy. By contrast, E2E1 knockdown aggravated the atrophying process in both catabolic C2C12 myotubes and the Tibialis anterior muscle of mice, suggesting that E2E1 has a protective effect on muscle mass. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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16 pages, 4062 KiB  
Article
Drosophila HUWE1 Ubiquitin Ligase Regulates Endoreplication and Antagonizes JNK Signaling During Salivary Gland Development
by Yifat Yanku, Eliya Bitman-Lotan, Yaniv Zohar, Estee Kurant, Norman Zilke, Martin Eilers and Amir Orian
Cells 2018, 7(10), 151; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7100151 - 26 Sep 2018
Cited by 6 | Viewed by 4756
Abstract
The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster [...] Read more.
The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster and Humans. Here, we report that the Drosophila ortholog, dHUWE1 (CG8184), is an essential gene whose loss results in embryonic lethality and whose tissue-specific disruption establishes its regulatory role in larval salivary gland development. dHUWE1 is essential for endoreplication of salivary gland cells and its knockdown results in the inability of these cells to replicate DNA. Remarkably, dHUWE1 is a survival factor that prevents premature activation of JNK signaling, thus preventing the disintegration of the salivary gland, which occurs physiologically during pupal stages. This function of dHUWE1 is general, as its inhibitory effect is observed also during eye development and at the organismal level. Epistatic studies revealed that the loss of dHUWE1 is compensated by dMyc proeitn expression or the loss of dmP53. dHUWE1 is therefore a conserved survival factor that regulates organ formation during Drosophila development. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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16 pages, 1661 KiB  
Article
The Effect of Neurotoxin MPTP and Neuroprotector Isatin on the Profile of Ubiquitinated Brain Mitochondrial Proteins
by Olga Buneeva, Arthur Kopylov, Inga Kapitsa, Elena Ivanova, Victor Zgoda and Alexei Medvedev
Cells 2018, 7(8), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7080091 - 31 Jul 2018
Cited by 22 | Viewed by 4450
Abstract
Mitochondria are a crucial target for the actions of neurotoxins, causing symptoms of Parkinson’s disease in various experimental animal models, and also neuroprotectors. There is evidence that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible [...] Read more.
Mitochondria are a crucial target for the actions of neurotoxins, causing symptoms of Parkinson’s disease in various experimental animal models, and also neuroprotectors. There is evidence that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria) and neuroprotective effects of certain anti-Parkisonian agents (monoamine oxidase inhibitors) may be associated with their effects on the UPS. In this study, we have investigated the effect of the neurotoxin MPTP and neuroprotector isatin, and their combination on the profile of ubiquitinated brain mitochondrial proteins. The development of movement disorders induced by MPTP administration caused dramatic changes in the profile of ubiquitinated proteins associated with mitochondria. Pretreatment with the neuroprotector isatin decreased manifestations of MPTP-induced Parkinsonism, and had a significant impact on the profile of ubiquitinated mitochondrial proteins (including oxidative modified proteins). Administration of isatin alone to intact mice also influenced the profile of ubiquitinated mitochondrial proteins, and increased the proportion of oxidized proteins carrying the ubiquitination signature. These alterations in the ubiquitination of mitochondrial proteins observed within 2 h after administration of MPTP and isatin obviously reflect immediate short-term biological responses to these treatments. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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Review

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16 pages, 1279 KiB  
Review
E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis
by Santina Venuto and Giuseppe Merla
Cells 2019, 8(5), 510; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050510 - 27 May 2019
Cited by 97 | Viewed by 8449
Abstract
The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while [...] Read more.
The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while chromosome segregation occurs during mitosis. During mitosis, the chromosomes are pulled into each of the two daughter cells by the coordination of spindle microtubules, kinetochores, centromeres, and chromatin. These four functional units tie chromosomes to the microtubules, send signals to the cells when the attachment is completed and the division can proceed, and withstand the force generated by pulling the chromosomes to either daughter cell. Protein ubiquitination is a post-translational modification that plays a central role in cellular homeostasis. E3 ubiquitin ligases mediate the transfer of ubiquitin to substrate proteins determining their fate. One of the largest subfamilies of E3 ubiquitin ligases is the family of the tripartite motif (TRIM) proteins, whose dysregulation is associated with a variety of cellular processes and directly involved in human diseases and cancer. In this review we summarize the current knowledge and emerging concepts about TRIMs and their contribution to the correct regulation of cell cycle, describing how TRIMs control the cell cycle transition phases and their involvement in the different functional units of the mitotic process, along with implications in cancer progression. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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20 pages, 1864 KiB  
Review
Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer
by Lucile M-P Jeusset and Kirk J McManus
Cells 2019, 8(2), 165; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8020165 - 16 Feb 2019
Cited by 37 | Viewed by 6503
Abstract
Histone ubiquitination is a critical epigenetic mechanism regulating DNA-driven processes such as gene transcription and DNA damage repair. Importantly, the cellular machinery regulating histone ubiquitination is frequently altered in cancers. Moreover, aberrant histone ubiquitination can drive oncogenesis by altering the expression of tumor [...] Read more.
Histone ubiquitination is a critical epigenetic mechanism regulating DNA-driven processes such as gene transcription and DNA damage repair. Importantly, the cellular machinery regulating histone ubiquitination is frequently altered in cancers. Moreover, aberrant histone ubiquitination can drive oncogenesis by altering the expression of tumor suppressors and oncogenes, misregulating cellular differentiation and promoting cancer cell proliferation. Thus, targeting aberrant histone ubiquitination may be a viable strategy to reprogram transcription in cancer cells, in order to halt cellular proliferation and induce cell death, which is the basis for the ongoing development of therapies targeting histone ubiquitination. In this review, we present the normal functions of histone H2A and H2B ubiquitination and describe the role aberrant histone ubiquitination has in oncogenesis. We also describe the key benefits and challenges associated with current histone ubiquitination targeting strategies. As these strategies are predicted to have off-target effects, we discuss additional efforts aimed at developing synthetic lethal strategies and epigenome editing tools, which may prove pivotal in achieving effective and selective therapies targeting histone ubiquitination, and ultimately improving the lives and outcomes of those living with cancer. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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17 pages, 1308 KiB  
Review
Control of DNA Replication Initiation by Ubiquitin
by Esperanza Hernández-Carralero, Elisa Cabrera, Ignacio Alonso-de Vega, Santiago Hernández-Pérez, Veronique A. J. Smits and Raimundo Freire
Cells 2018, 7(10), 146; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7100146 - 20 Sep 2018
Cited by 11 | Viewed by 5724
Abstract
Eukaryotic cells divide by accomplishing a program of events in which the replication of the genome is a fundamental part. To ensure all cells have an accurate copy of the genome, DNA replication occurs only once per cell cycle and is controlled by [...] Read more.
Eukaryotic cells divide by accomplishing a program of events in which the replication of the genome is a fundamental part. To ensure all cells have an accurate copy of the genome, DNA replication occurs only once per cell cycle and is controlled by numerous pathways. A key step in this process is the initiation of DNA replication in which certain regions of DNA are marked as competent to replicate. Moreover, initiation of DNA replication needs to be coordinated with other cell cycle processes. At the molecular level, initiation of DNA replication relies, among other mechanisms, upon post-translational modifications, including the conjugation and hydrolysis of ubiquitin. An example is the precise control of the levels of the DNA replication initiation protein Cdt1 and its inhibitor Geminin by ubiquitin-mediated proteasomal degradation. This control ensures that DNA replication occurs with the right timing during the cell cycle, thereby avoiding re-replication events. Here, we review the events that involve ubiquitin signalling during DNA replication initiation, and how they are linked to human disease. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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19 pages, 1009 KiB  
Review
Ubiquitin Regulation: The Histone Modifying Enzyme′s Story
by Jianlin Wang, Zhaoping Qiu and Yadi Wu
Cells 2018, 7(9), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7090118 - 27 Aug 2018
Cited by 17 | Viewed by 8890
Abstract
Histone post-translational modifications influence many fundamental cellular events by regulating chromatin structure and gene transcriptional activity. These modifications are highly dynamic and tightly controlled, with many enzymes devoted to the addition and removal of these modifications. Interestingly, these modifying enzymes are themselves fine-tuned [...] Read more.
Histone post-translational modifications influence many fundamental cellular events by regulating chromatin structure and gene transcriptional activity. These modifications are highly dynamic and tightly controlled, with many enzymes devoted to the addition and removal of these modifications. Interestingly, these modifying enzymes are themselves fine-tuned and precisely regulated at the level of protein turnover by ubiquitin-proteasomal processing. Here, we focus on recent progress centered on the mechanisms regulating ubiquitination of histone modifying enzymes, including ubiquitin proteasomal degradation and the reverse process of deubiquitination. We will also discuss the potential pathophysiological significance of these processes. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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24 pages, 1757 KiB  
Review
Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?
by Anne-Claire Jacomin, Emmanuel Taillebourg and Marie-Odile Fauvarque
Cells 2018, 7(8), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7080112 - 19 Aug 2018
Cited by 31 | Viewed by 7804
Abstract
Autophagy is an evolutionary conserved catabolic process that allows for the degradation of intracellular components by lysosomes. This process can be triggered by nutrient deprivation, microbial infections or other challenges to promote cell survival under these stressed conditions. However, basal levels of autophagy [...] Read more.
Autophagy is an evolutionary conserved catabolic process that allows for the degradation of intracellular components by lysosomes. This process can be triggered by nutrient deprivation, microbial infections or other challenges to promote cell survival under these stressed conditions. However, basal levels of autophagy are also crucial for the maintenance of proper cellular homeostasis by ensuring the selective removal of protein aggregates and dysfunctional organelles. A tight regulation of this process is essential for cellular survival and organismal health. Indeed, deregulation of autophagy is associated with a broad range of pathologies such as neuronal degeneration, inflammatory diseases, and cancer progression. Ubiquitination and deubiquitination of autophagy substrates, as well as components of the autophagic machinery, are critical regulatory mechanisms of autophagy. Here, we review the main evidence implicating deubiquitinating enzymes (DUBs) in the regulation of autophagy. We also discuss how they may constitute new therapeutic opportunities in the treatment of pathologies such as cancers, neurodegenerative diseases or infections. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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17 pages, 1815 KiB  
Review
Lafora Disease: A Ubiquitination-Related Pathology
by Maria Adelaida García-Gimeno, Erwin Knecht and Pascual Sanz
Cells 2018, 7(8), 87; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7080087 - 26 Jul 2018
Cited by 31 | Viewed by 8128
Abstract
Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named [...] Read more.
Lafora disease (LD, OMIM254780) is a rare and fatal form of progressive myoclonus epilepsy (PME). Among PMEs, LD is unique because of the rapid neurological deterioration of the patients and the appearance in brain and peripheral tissues of insoluble glycogen-like (polyglucosan) inclusions, named Lafora bodies (LBs). LD is caused by mutations in the EPM2A gene, encoding the dual phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Laforin and malin form a functional complex that is involved in the regulation of glycogen synthesis. Thus, in the absence of a functional complex glycogen accumulates in LBs. In addition, it has been suggested that the laforin-malin complex participates in alternative physiological pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response. In this work we review the possible cellular functions of laforin and malin with a special focus on their role in the ubiquitination of specific substrates. We also discuss here the pathological consequences of defects in laforin or malin functions, as well as the therapeutic strategies that are being explored for LD. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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Other

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1 pages, 191 KiB  
Erratum
Erratum: Polge, C., et al. UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment. Cells 2018, 7, 214
by Cécile Polge, Julien Aniort, Andrea Armani, Agnès Claustre, Cécile Coudy-Gandilhon, Clara Tournebize, Christiane Deval, Lydie Combaret, Daniel Béchet, Marco Sandri, Didier Attaix and Daniel Taillandier
Cells 2018, 7(12), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/cells7120242 - 04 Dec 2018
Cited by 7 | Viewed by 2260
Abstract
Change in author names (order). [...] Full article
(This article belongs to the Special Issue Ubiquitination in Health and Disease)
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