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Special Issue "Ubiquitin and Ubiquitin-Like Proteins: From Basic Mechanisms to Human Disorders"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 15055

Special Issue Editors

Dr. Cécile Polge
E-Mail Website1 Website2
Guest Editor
INRA, University of Clermont - Auvergne, Department of Human Nutrition, St Genès Champanelle, France
Interests: muscle atrophy; cachexia; ubiquitin; ubiquitinating enzymes; proteasome
Prof. Dr. Alfred Vertegaal
E-Mail Website
Guest Editor
Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Interests: SUMO; small ubiquitin-like modifiers; SUMO-2

Special Issue Information

Dear Colleagues,

Eukaryotic proteins can be modified by a variety of post-translational modifications (PTM) such as phosphorylation, acetylation, methylation, etc. Among these, ubiquitination is a widespread PTM and corresponds to the transient attachment of ubiquitin (UB), a small protein (8.6 kDa) conserved among the Eukaryota. Since three decades, other protein modifiers, called ubiquitin-like proteins (UBL), have been identified, presenting significant sequence similarity to ubiquitin (e.g., SUMO, NEDD8, ISG15, FAT10, etc.). UB and UBL are attached to proteins by similar enzymatic cascades and form multiple types of monomeric or polymeric-chain PTM. These different types of PTM determine the fate of a protein (protein degradation, localization, interactions, and activity). UB and some UBL marks can be further modified by additional post-translational modifications, such as phosphorylation, or reversed (e.g., by deubiquitinases, DUBs). UB and UBL regulate many cellular processes, and, not surprisingly, dysregulation of this system (e.g., mutations in the enzymatic cascade or DUBs) is associated with many pathologies. This Special Issue aims to identify and review the latest advances in the field and illustrate the therapeutic prospects of targeting the ubiquitinating and deubiquitinating enzymes in human diseases.

Dr. Cécile Polge
Dr. Alfred Vertegaal
Guest Editors

Manuscript Submission Information

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Keywords

  • Ubiquitin
  • Ubiquitin-like proteins
  • Ubiquitinating enzymes (E1, E2, E3)
  • Deubitinases (DUBs)
  • Human pathologies

Published Papers (9 papers)

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Research

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Article
The UFM1 Pathway Impacts HCMV US2-Mediated Degradation of HLA Class I
Molecules 2021, 26(2), 287; https://doi.org/10.3390/molecules26020287 - 08 Jan 2021
Cited by 1 | Viewed by 1403
Abstract
To prevent accumulation of misfolded proteins in the endoplasmic reticulum, chaperones perform quality control on newly translated proteins and redirect misfolded proteins to the cytosol for degradation by the ubiquitin-proteasome system. This pathway is called ER-associated protein degradation (ERAD). The human cytomegalovirus protein [...] Read more.
To prevent accumulation of misfolded proteins in the endoplasmic reticulum, chaperones perform quality control on newly translated proteins and redirect misfolded proteins to the cytosol for degradation by the ubiquitin-proteasome system. This pathway is called ER-associated protein degradation (ERAD). The human cytomegalovirus protein US2 induces accelerated ERAD of HLA class I molecules to prevent immune recognition of infected cells by CD8+ T cells. Using US2-mediated HLA-I degradation as a model for ERAD, we performed a genome-wide CRISPR/Cas9 library screen to identify novel cellular factors associated with ERAD. Besides the identification of known players such as TRC8, p97, and UBE2G2, the ubiquitin-fold modifier1 (UFM1) pathway was found to affect degradation of HLA-I. UFMylation is a post-translational modification resembling ubiquitination. Whereas we observe ubiquitination of HLA-I, no UFMylation was detected on HLA-I or several other proteins involved in degradation of HLA-I, suggesting that the UFM1 pathway impacts ERAD in a different manner than ubiquitin. Interference with the UFM1 pathway seems to specifically inhibit the ER-to-cytosol dislocation of HLA-I. In the absence of detectable UFMylation of HLA-I, UFM1 may contribute to US2-mediated HLA-I degradation by misdirecting protein sorting indirectly. Mass spectrometry analysis of US2-expressing cells showed that ribosomal proteins are a major class of proteins undergoing extensive UFMylation; the role of these changes in protein degradation may be indirect and remains to be established. Full article
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Article
Profiling the Murine SUMO Proteome in Response to Cardiac Ischemia and Reperfusion Injury
Molecules 2020, 25(23), 5571; https://doi.org/10.3390/molecules25235571 - 27 Nov 2020
Cited by 6 | Viewed by 1114
Abstract
SUMOylation is a reversible posttranslational modification pathway catalyzing the conjugation of small ubiquitin-related modifier (SUMO) proteins to lysine residues of distinct target proteins. SUMOylation modifies a wide variety of cellular regulators thereby affecting a multitude of key processes in a highly dynamic manner. [...] Read more.
SUMOylation is a reversible posttranslational modification pathway catalyzing the conjugation of small ubiquitin-related modifier (SUMO) proteins to lysine residues of distinct target proteins. SUMOylation modifies a wide variety of cellular regulators thereby affecting a multitude of key processes in a highly dynamic manner. The SUMOylation pathway displays a hallmark in cellular stress-adaption, such as heat or redox stress. It has been proposed that enhanced cellular SUMOylation protects the brain during ischemia, however, little is known about the specific regulation of the SUMO system and the potential target proteins during cardiac ischemia and reperfusion injury (I/R). By applying left anterior descending (LAD) coronary artery ligation and reperfusion in mice, we detect dynamic changes in the overall cellular SUMOylation pattern correlating with decreased SUMO deconjugase activity during I/R injury. Further, unbiased system-wide quantitative SUMO-proteomics identified a sub-group of SUMO targets exhibiting significant alterations in response to cardiac I/R. Notably, transcription factors that control hypoxia- and angiogenesis-related gene expression programs, exhibit altered SUMOylation during ischemic stress adaptation. Moreover, several components of the ubiquitin proteasome system undergo dynamic changes in SUMO conjugation during cardiac I/R suggesting an involvement of SUMO signaling in protein quality control and proteostasis in the ischemic heart. Altogether, our study reveals regulated candidate SUMO target proteins in the mouse heart, which might be important in coping with hypoxic/proteotoxic stress during cardiac I/R injury. Full article
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Review

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Review
SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies
Molecules 2021, 26(4), 828; https://doi.org/10.3390/molecules26040828 - 05 Feb 2021
Cited by 15 | Viewed by 1625
Abstract
One major role of the eukaryotic peptidic post-translational modifier SUMO in the cell is transcriptional control. This occurs via modification of virtually all classes of transcriptional actors, which include transcription factors, transcriptional coregulators, diverse chromatin components, as well as Pol I-, Pol II- [...] Read more.
One major role of the eukaryotic peptidic post-translational modifier SUMO in the cell is transcriptional control. This occurs via modification of virtually all classes of transcriptional actors, which include transcription factors, transcriptional coregulators, diverse chromatin components, as well as Pol I-, Pol II- and Pol III transcriptional machineries and their regulators. For many years, the role of SUMOylation has essentially been studied on individual proteins, or small groups of proteins, principally dealing with Pol II-mediated transcription. This provided only a fragmentary view of how SUMOylation controls transcription. The recent advent of large-scale proteomic, modifomic and genomic studies has however considerably refined our perception of the part played by SUMO in gene expression control. We review here these developments and the new concepts they are at the origin of, together with the limitations of our knowledge. How they illuminate the SUMO-dependent transcriptional mechanisms that have been characterized thus far and how they impact our view of SUMO-dependent chromatin organization are also considered. Full article
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Review
Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control
Molecules 2021, 26(2), 407; https://doi.org/10.3390/molecules26020407 - 14 Jan 2021
Cited by 12 | Viewed by 1820
Abstract
Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a [...] Read more.
Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies. Full article
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Review
The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents
Molecules 2020, 25(24), 5956; https://doi.org/10.3390/molecules25245956 - 16 Dec 2020
Cited by 6 | Viewed by 1952
Abstract
The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction [...] Read more.
The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline. Full article
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Review
The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family
Molecules 2020, 25(24), 5938; https://doi.org/10.3390/molecules25245938 - 15 Dec 2020
Cited by 2 | Viewed by 1114
Abstract
The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of [...] Read more.
The ligand of Numb protein-X (LNX) family, also known as the PDZRN family, is composed of four discrete RING-type E3 ubiquitin ligases (LNX1, LNX2, LNX3, and LNX4), and LNX5 which may not act as an E3 ubiquitin ligase owing to the lack of the RING domain. As the name implies, LNX1 and LNX2 were initially studied for exerting E3 ubiquitin ligase activity on their substrate Numb protein, whose stability was negatively regulated by LNX1 and LNX2 via the ubiquitin-proteasome pathway. LNX proteins may have versatile molecular, cellular, and developmental functions, considering the fact that besides these proteins, none of the E3 ubiquitin ligases have multiple PDZ (PSD95, DLGA, ZO-1) domains, which are regarded as important protein-interacting modules. Thus far, various proteins have been isolated as LNX-interacting proteins. Evidence from studies performed over the last two decades have suggested that members of the LNX family play various pathophysiological roles primarily by modulating the function of substrate proteins involved in several different intracellular or intercellular signaling cascades. As the binding partners of RING-type E3s, a large number of substrates of LNX proteins undergo degradation through ubiquitin-proteasome system (UPS) dependent or lysosomal pathways, potentially altering key signaling pathways. In this review, we highlight recent and relevant findings on the molecular and cellular functions of the members of the LNX family and discuss the role of the erroneous regulation of these proteins in disease progression. Full article
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Review
The Role of Conformational Dynamics in the Recognition and Regulation of Ubiquitination
Molecules 2020, 25(24), 5933; https://doi.org/10.3390/molecules25245933 - 15 Dec 2020
Cited by 3 | Viewed by 890
Abstract
The ubiquitination pathway is central to many cell signaling and regulatory events. One of the intriguing aspects of the pathway is the combinatorial sophistication of substrate recognition and ubiquitin chain building determinations. The abundant structural and biological data portray several characteristic protein folds [...] Read more.
The ubiquitination pathway is central to many cell signaling and regulatory events. One of the intriguing aspects of the pathway is the combinatorial sophistication of substrate recognition and ubiquitin chain building determinations. The abundant structural and biological data portray several characteristic protein folds among E2 and E3 proteins, and the understanding of the combinatorial complexity that enables interaction with much of the human proteome is a major goal to developing targeted and selective manipulation of the pathway. With the commonality of some folds, there are likely other aspects that can provide differentiation and recognition. These aspects involve allosteric effects and conformational dynamics that can direct recognition and chain building processes. In this review, we will describe the current state of the knowledge for conformational dynamics across a wide timescale, address the limitations of present approaches, and illustrate the potential to make new advances in connecting dynamics with ubiquitination regulation. Full article
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Review
Branched Ubiquitination: Detection Methods, Biological Functions and Chemical Synthesis
Molecules 2020, 25(21), 5200; https://doi.org/10.3390/molecules25215200 - 09 Nov 2020
Cited by 6 | Viewed by 2180
Abstract
Ubiquitination is a versatile posttranslational modification that elicits signaling roles to impact on various cellular processes and disease states. The versatility is a result of the complexity of ubiquitin conjugates, ranging from a single ubiquitin monomer to polymers with different length and linkage [...] Read more.
Ubiquitination is a versatile posttranslational modification that elicits signaling roles to impact on various cellular processes and disease states. The versatility is a result of the complexity of ubiquitin conjugates, ranging from a single ubiquitin monomer to polymers with different length and linkage types. Recent studies have revealed the abundant existence of branched ubiquitin chains in which one ubiquitin molecule is connected to two or more ubiquitin moieties in the same ubiquitin polymer. Compared to the homotypic ubiquitin chain, the branched chain is recognized or processed differently by readers and erasers of the ubiquitin system, respectively, resulting in a qualitative or quantitative alteration of the functional output. Furthermore, certain types of branched ubiquitination are induced by cellular stresses, implicating their important physiological role in stress adaption. In addition, the current chemical methodologies of solid phase peptide synthesis and expanding genetic code approach have been developed to synthesize different architectures of branched ubiquitin chains. The synthesized branched ubiquitin chains have shown their significance in understanding the topologies and binding partners of the branched chains. Here, we discuss the recent progresses on the detection, functional characterization and synthesis of branched ubiquitin chains as well as the future perspectives of this emerging field. Full article
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Review
Mechanisms Regulating the UPS-ALS Crosstalk: The Role of Proteaphagy
Molecules 2020, 25(10), 2352; https://doi.org/10.3390/molecules25102352 - 18 May 2020
Cited by 12 | Viewed by 2369
Abstract
Protein degradation is tightly regulated inside cells because of its utmost importance for protein homeostasis (proteostasis). The two major intracellular proteolytic pathways are the ubiquitin-proteasome and the autophagy-lysosome systems which ensure the fate of proteins when modified by various members of the ubiquitin [...] Read more.
Protein degradation is tightly regulated inside cells because of its utmost importance for protein homeostasis (proteostasis). The two major intracellular proteolytic pathways are the ubiquitin-proteasome and the autophagy-lysosome systems which ensure the fate of proteins when modified by various members of the ubiquitin family. These pathways are tightly interconnected by receptors and cofactors that recognize distinct chain architectures to connect with either the proteasome or autophagy under distinct physiologic and pathologic situations. The degradation of proteasome by autophagy, known as proteaphagy, plays an important role in this crosstalk since it favours the activity of autophagy in the absence of fully active proteasomes. Recently described in several biological models, proteaphagy appears to help the cell to survive when proteostasis is broken by the absence of nutrients or the excess of proteins accumulated under various stress conditions. Emerging evidence indicates that proteaphagy could be permanently activated in some types of cancer or when chemoresistance is observed in patients. Full article
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