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Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling
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Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (20 December 2020) | Viewed by 82316

Special Issue Editor

Dr. Elah Pick

E-Mail Website
Guest Editor
Department of Biology and Environment, University of Haifa, Haifa, Israel
Interests: maintenance of protein homeostasis; cullin-NEDD8 cycles; cellular responses to oxidative stress; replicative ageing in the model organism Saccharomyces cerevisiae

Special Issue Information

Dear Colleagues,

The reversible modification of proteins or lipids by ubiquitin-like proteins (UbLs) is a key regulatory process in virtually all aspects of cell physiology. UbLs target thousands of cellular components through homologous and sometimes parallel modification pathways. Together, UbLs constitute an elaborate code involved in multiple intracellular pathways, including general protein turnover, cell cycle progression, transcription, morphogenesis and development, responses to environmental challenges, and enhanced immune response. Aberrations in the UbL code are implicated in multiple human diseases such as cancer, neurodegeneration, developmental and aging disorders, as well as in plant responses to environmental stresses, including pathogen infection, drought, salinity, temperature changes, nutrient deprivation, irradiation and pollution. Recent technological advances in gene manipulations, high-resolution microscopy, mass spectrometry, chemical synthesis, and stem cell utilization coalesce to contribute to potential therapeutic interventions. This Special Issue shares the fantastic recent progress in the field, together with pioneering discoveries.

Dr. Elah Pick
Guest Editor

Manuscript Submission Information

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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-like proteins
  • Ubiquitin
  • NEDD8/Rub1
  • SUMO
  • ISG15
  • FAT10
  • UFM1
  • ATG8
  • ATG12
  • URM1
  • Proteostasis
  • Oxidative stress
  • Redox signaling
  • Protein quality control

Published Papers (18 papers)

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Research

Jump to: Review

17 pages, 5518 KiB  
Article
Saccharomyces cerevisiae as a Toolkit for COP9 Signalosome Research
by Dana Harshuk-Shabso, Noam Castel, Ran Israeli, Sheri Harari and Elah Pick
Biomolecules 2021, 11(4), 497; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11040497 - 25 Mar 2021
Viewed by 2026
Abstract
The COP9 signalosome (CSN) is a highly conserved eukaryotic multi-subunit enzyme, regulating cullin RING ligase activities and accordingly, substrate ubiquitination and degradation. We showed that the CSN complex of Saccharomyces cerevisiae that is deviated in subunit composition and in sequence homology harbors a [...] Read more.
The COP9 signalosome (CSN) is a highly conserved eukaryotic multi-subunit enzyme, regulating cullin RING ligase activities and accordingly, substrate ubiquitination and degradation. We showed that the CSN complex of Saccharomyces cerevisiae that is deviated in subunit composition and in sequence homology harbors a highly conserved cullin deneddylase enzymatic core complex. We took advantage of the non-essentiality of the S. cerevisiae CSN-NEDD8/Rub1 axis, together with the enzyme-substrate cross-species activity, to develop a sensitive fluorescence readout assay, suitable for biochemical assessment of cullin deneddylation by CSNs from various origins. We also demonstrated that the yeast catalytic subunit, CSN5/Jab1, is targeted by an inhibitor that was selected for the human orthologue. Treatment of yeast by the inhibitor led to the accumulation of neddylated cullins and the formation of reactive oxygen species. Overall, our data revealed S. cerevisiae as a general platform that can be used for studies of CSN deneddylation and for testing the efficacy of selected CSN inhibitors. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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16 pages, 4123 KiB  
Article
USP25 Regulates EGFR Fate by Modulating EGF-Induced Ubiquitylation Dynamics
by Carlos A. Niño, Nadine Wollscheid, Giovanni Giangreco, Elena Maspero and Simona Polo
Biomolecules 2020, 10(11), 1548; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111548 - 13 Nov 2020
Cited by 8 | Viewed by 2786
Abstract
Deregulated epidermal growth factor receptor (EGFR) signaling is a key feature in different stages of oncogenesis. One important mechanism whereby cancer cells achieve increased and uncontrolled EGFR signaling is escaping down-modulation of the receptor. Ubiquitylation of the EGFR plays a decisive role in [...] Read more.
Deregulated epidermal growth factor receptor (EGFR) signaling is a key feature in different stages of oncogenesis. One important mechanism whereby cancer cells achieve increased and uncontrolled EGFR signaling is escaping down-modulation of the receptor. Ubiquitylation of the EGFR plays a decisive role in this process, as it regulates receptor internalization, trafficking and degradation. Deubiquitinating enzymes (DUBs) may oppose the ubiquitylation process, antagonizing or even promoting receptor degradation. Here, we use qualitative and quantitative assays to measure EGFR internalization and degradation after Ubiquitin Specific Peptidase 25 (USP25) depletion. We show that, by acting at the early steps of EGFR internalization, USP25 restrains the degradation of the EGFR by assisting in the association of the E3 ubiquitin ligase c-Cbl with EGFR, thereby modulating the amplitude of ubiquitylation on the receptor. This study establishes USP25 as a negative regulator of the EGFR down-modulation process and suggests that it is a promising target for pharmacological intervention to hamper oncogenic growth signals in tumors that depend on the EGFR. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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Review

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28 pages, 1380 KiB  
Review
The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins
by Meytal Radzinski, Tal Oppenheim, Norman Metanis and Dana Reichmann
Biomolecules 2021, 11(3), 469; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11030469 - 22 Mar 2021
Cited by 14 | Viewed by 6384
Abstract
Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, [...] Read more.
Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, cell damage, and death. This merges together the processes of protein homeostasis and redox regulation. At the heart of this process are redox-regulated proteins or thiol-based switches, which carefully mediate various steps of protein homeostasis across folding, localization, quality control, and degradation pathways. In this review, we discuss the “redox code” of the proteostasis network, which shapes protein health during cell growth and aging. We describe the sources and types of thiol modifications and elaborate on diverse strategies of evolving antioxidant proteins in proteostasis networks during oxidative stress conditions. We also highlight the involvement of cysteines in protein degradation across varying levels, showcasing the importance of cysteine thiols in proteostasis at large. The individual examples and mechanisms raised open the door for extensive future research exploring the interplay between the redox and protein homeostasis systems. Understanding this interplay will enable us to re-write the redox code of cells and use it for biotechnological and therapeutic purposes. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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15 pages, 1440 KiB  
Review
Urm1: A Non-Canonical UBL
by Martin Termathe and Sebastian A. Leidel
Biomolecules 2021, 11(2), 139; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11020139 - 22 Jan 2021
Cited by 7 | Viewed by 3746
Abstract
Urm1 (ubiquitin related modifier 1) is a molecular fossil in the class of ubiquitin-like proteins (UBLs). It encompasses characteristics of classical UBLs, such as ubiquitin or SUMO (small ubiquitin-related modifier), but also of bacterial sulfur-carrier proteins (SCP). Since its main function is to [...] Read more.
Urm1 (ubiquitin related modifier 1) is a molecular fossil in the class of ubiquitin-like proteins (UBLs). It encompasses characteristics of classical UBLs, such as ubiquitin or SUMO (small ubiquitin-related modifier), but also of bacterial sulfur-carrier proteins (SCP). Since its main function is to modify tRNA, Urm1 acts in a non-canonical manner. Uba4, the activating enzyme of Urm1, contains two domains: a classical E1-like domain (AD), which activates Urm1, and a rhodanese homology domain (RHD). This sulfurtransferase domain catalyzes the formation of a C-terminal thiocarboxylate on Urm1. Thiocarboxylated Urm1 is the sulfur donor for 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), a chemical nucleotide modification at the wobble position in tRNA. This thio-modification is conserved in all domains of life and optimizes translation. The absence of Urm1 increases stress sensitivity in yeast triggered by defects in protein homeostasis, a hallmark of neurological defects in higher organisms. In contrast, elevated levels of tRNA modifying enzymes promote the appearance of certain types of cancer and the formation of metastasis. Here, we summarize recent findings on the unique features that place Urm1 at the intersection of UBL and SCP and make Urm1 an excellent model for studying the evolution of protein conjugation and sulfur-carrier systems. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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16 pages, 1103 KiB  
Review
Evolution and Adaptation of Legionella pneumophila to Manipulate the Ubiquitination Machinery of Its Amoebae and Mammalian Hosts
by Christopher T.D. Price and Yousef Abu Kwaik
Biomolecules 2021, 11(1), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010112 - 15 Jan 2021
Cited by 11 | Viewed by 3334
Abstract
The ubiquitin pathway is highly conserved across the eukaryotic domain of life and plays an essential role in a plethora of cellular processes. It is not surprising that many intracellular bacterial pathogens often target the essential host ubiquitin pathway. The intracellular bacterial pathogen [...] Read more.
The ubiquitin pathway is highly conserved across the eukaryotic domain of life and plays an essential role in a plethora of cellular processes. It is not surprising that many intracellular bacterial pathogens often target the essential host ubiquitin pathway. The intracellular bacterial pathogen Legionella pneumophila injects into the host cell cytosol multiple classes of classical and novel ubiquitin-modifying enzymes that modulate diverse ubiquitin-related processes in the host cell. Most of these pathogen-injected proteins, designated as effectors, mimic known E3-ubiquitin ligases through harboring F-box or U-box domains. The classical F-box effector, AnkB targets host proteins for K48-linked polyubiquitination, which leads to excessive proteasomal degradation that is required to generate adequate supplies of amino acids for metabolism of the pathogen. In contrast, the SidC and SdcA effectors share no structural similarity to known eukaryotic ligases despite having E3-ubiquitin ligase activity, suggesting that the number of E3-ligases in eukaryotes is under-represented. L. pneumophila also injects into the host many novel ubiquitin-modifying enzymes, which are the SidE family of effectors that catalyze phosphoribosyl-ubiquitination of serine residue of target proteins, independently of the canonical E1-2-3 enzymatic cascade. Interestingly, the environmental bacterium, L. pneumophila, has evolved within a diverse range of amoebal species, which serve as the natural hosts, while accidental transmission through contaminated aerosols can cause pneumonia in humans. Therefore, it is likely that the novel ubiquitin-modifying enzymes of L. pneumophila were acquired by the pathogen through interkingdom gene transfer from the diverse natural amoebal hosts. Furthermore, conservation of the ubiquitin pathway across eukaryotes has enabled these novel ubiquitin-modifying enzymes to function similarly in mammalian cells. Studies on the biological functions of these effectors are likely to reveal further novel ubiquitin biology and shed further lights on the evolution of ubiquitin. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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16 pages, 864 KiB  
Review
Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance
by Dina Franić, Klara Zubčić and Mirta Boban
Biomolecules 2021, 11(1), 54; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010054 - 04 Jan 2021
Cited by 23 | Viewed by 4562
Abstract
Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and [...] Read more.
Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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15 pages, 905 KiB  
Review
Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability
by Prasad Sulkshane, Jonathan Ram and Michael H Glickman
Biomolecules 2020, 10(11), 1559; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111559 - 16 Nov 2020
Cited by 15 | Viewed by 4083
Abstract
Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and [...] Read more.
Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and thus, for viability. In addition to internal mitochondrial chaperones and proteases, mitochondrial health is also governed by host cell protein quality control systems. The ubiquitin-proteasome system (UPS) and autophagy constitute the main pathways for removal of damaged or superfluous proteins in the cytosol, nucleus, and from certain organelles such as the Endoplasmic Reticulum (ER) and mitochondria. Although stress-induced ubiquitin-dependent degradation of mitochondrial outer membrane proteins has been widely studied, mechanisms of intramitochondrial protein ubiquitination has remained largely elusive due to the predominantly cytosolic nature of UPS components, separated from internal mitochondrial proteins by a double membrane. However, recent research has illuminated examples of intramitochondrial protein ubiquitination pathways and highlighted their importance under basal and stressful conditions. Owing to the dependence of mitochondria on the error-prone process of protein import from the cytosol, it is imperative that the cell eliminate any accumulated proteins in the event of mitochondrial protein import deficiency. Apparently, a significant portion of this activity involves ubiquitination in one way or another. In the present review article, following a brief introduction to mitochondrial protein quality control mechanisms, we discuss our recent understanding of intramitochondrial protein ubiquitination, its importance for basal function of mitochondria, metabolic implications, and possible therapeutic applications. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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30 pages, 6248 KiB  
Review
More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond
by Zac Sandy, Isabelle Cristine da Costa and Christine K. Schmidt
Biomolecules 2020, 10(11), 1557; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111557 - 15 Nov 2020
Cited by 32 | Viewed by 7250
Abstract
Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical [...] Read more.
Maintenance of genome stability is a crucial priority for any organism. To meet this priority, robust signalling networks exist to facilitate error-free DNA replication and repair. These signalling cascades are subject to various regulatory post-translational modifications that range from simple additions of chemical moieties to the conjugation of ubiquitin-like proteins (UBLs). Interferon Stimulated Gene 15 (ISG15) is one such UBL. While classically thought of as a component of antiviral immunity, ISG15 has recently emerged as a regulator of genome stability, with key roles in the DNA damage response (DDR) to modulate p53 signalling and error-free DNA replication. Additional proteomic analyses and cancer-focused studies hint at wider-reaching, uncharacterised functions for ISG15 in genome stability. We review these recent discoveries and highlight future perspectives to increase our understanding of this multifaceted UBL in health and disease. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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25 pages, 2742 KiB  
Review
RNF11 at the Crossroads of Protein Ubiquitination
by Anna Mattioni, Luisa Castagnoli and Elena Santonico
Biomolecules 2020, 10(11), 1538; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111538 - 11 Nov 2020
Cited by 6 | Viewed by 3046
Abstract
RNF11 (Ring Finger Protein 11) is a 154 amino-acid long protein that contains a RING-H2 domain, whose sequence has remained substantially unchanged throughout vertebrate evolution. RNF11 has drawn attention as a modulator of protein degradation by HECT E3 ligases. Indeed, the large number [...] Read more.
RNF11 (Ring Finger Protein 11) is a 154 amino-acid long protein that contains a RING-H2 domain, whose sequence has remained substantially unchanged throughout vertebrate evolution. RNF11 has drawn attention as a modulator of protein degradation by HECT E3 ligases. Indeed, the large number of substrates that are regulated by HECT ligases, such as ITCH, SMURF1/2, WWP1/2, and NEDD4, and their role in turning off the signaling by ubiquitin-mediated degradation, candidates RNF11 as the master regulator of a plethora of signaling pathways. Starting from the analysis of the primary sequence motifs and from the list of RNF11 protein partners, we summarize the evidence implicating RNF11 as an important player in modulating ubiquitin-regulated processes that are involved in transforming growth factor beta (TGF-β), nuclear factor-κB (NF-κB), and Epidermal Growth Factor (EGF) signaling pathways. This connection appears to be particularly significant, since RNF11 is overexpressed in several tumors, even though its role as tumor growth inhibitor or promoter is still controversial. The review highlights the different facets and peculiarities of this unconventional small RING-E3 ligase and its implication in tumorigenesis, invasion, neuroinflammation, and cancer metastasis. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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21 pages, 8841 KiB  
Review
BRCA1-A and BRISC: Multifunctional Molecular Machines for Ubiquitin Signaling
by Julius Rabl
Biomolecules 2020, 10(11), 1503; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111503 - 31 Oct 2020
Cited by 14 | Viewed by 4963
Abstract
The K63-linkage specific deubiquitinase BRCC36 forms the core of two multi-subunit deubiquitination complexes: BRCA1-A and BRISC. BRCA1-A is recruited to DNA repair foci, edits ubiquitin signals on chromatin, and sequesters BRCA1 away from the site of damage, suppressing homologous recombination by limiting [...] Read more.
The K63-linkage specific deubiquitinase BRCC36 forms the core of two multi-subunit deubiquitination complexes: BRCA1-A and BRISC. BRCA1-A is recruited to DNA repair foci, edits ubiquitin signals on chromatin, and sequesters BRCA1 away from the site of damage, suppressing homologous recombination by limiting resection. BRISC forms a complex with metabolic enzyme SHMT2 and regulates the immune response, mitosis, and hematopoiesis. Almost two decades of research have revealed how BRCA1-A and BRISC use the same core of subunits to perform very distinct biological tasks. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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14 pages, 1328 KiB  
Review
Decrypting UFMylation: How Proteins Are Modified with UFM1
by Sayanika Banerjee, Manoj Kumar and Reuven Wiener
Biomolecules 2020, 10(10), 1442; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101442 - 14 Oct 2020
Cited by 32 | Viewed by 7390
Abstract
Besides ubiquitin (Ub), humans have a set of ubiquitin-like proteins (UBLs) that can also covalently modify target proteins. To date, less is known about UBLs than Ub and even less is known about the UBL called ubiquitin-fold modifier 1 (UFM1). Currently, our understanding [...] Read more.
Besides ubiquitin (Ub), humans have a set of ubiquitin-like proteins (UBLs) that can also covalently modify target proteins. To date, less is known about UBLs than Ub and even less is known about the UBL called ubiquitin-fold modifier 1 (UFM1). Currently, our understanding of protein modification by UFM1 (UFMylation) is like a jigsaw puzzle with many missing pieces, and in some cases it is not even clear whether these pieces of data are in the right place. Here we review the current data on UFM1 from structural biology to biochemistry and cell biology. We believe that the physiological significance of protein modification by UFM1 is currently underestimated and there is more to it than meets the eye. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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20 pages, 1393 KiB  
Review
Ubiquitin-Like Modifiers: Emerging Regulators of Protozoan Parasites
by Maryia Karpiyevich and Katerina Artavanis-Tsakonas
Biomolecules 2020, 10(10), 1403; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101403 - 03 Oct 2020
Cited by 14 | Viewed by 5567
Abstract
Post-translational protein regulation allows for fine-tuning of cellular functions and involves a wide range of modifications, including ubiquitin and ubiquitin-like modifiers (Ubls). The dynamic balance of Ubl conjugation and removal shapes the fates of target substrates, in turn modulating various cellular processes. The [...] Read more.
Post-translational protein regulation allows for fine-tuning of cellular functions and involves a wide range of modifications, including ubiquitin and ubiquitin-like modifiers (Ubls). The dynamic balance of Ubl conjugation and removal shapes the fates of target substrates, in turn modulating various cellular processes. The mechanistic aspects of Ubl pathways and their biological roles have been largely established in yeast, plants, and mammalian cells. However, these modifiers may be utilised differently in highly specialised and divergent organisms, such as parasitic protozoa. In this review, we explore how these parasites employ Ubls, in particular SUMO, NEDD8, ATG8, ATG12, URM1, and UFM1, to regulate their unconventional cellular physiology. We discuss emerging data that provide evidence of Ubl-mediated regulation of unique parasite-specific processes, as well as the distinctive features of Ubl pathways in parasitic protozoa. We also highlight the potential to leverage these essential regulators and their cognate enzymatic machinery for development of therapeutics to protect against the diseases caused by protozoan parasites. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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11 pages, 1358 KiB  
Review
Releasing the Lockdown: An Emerging Role for the Ubiquitin-Proteasome System in the Breakdown of Transient Protein Inclusions
by Yuval Reiss, Elisheva Gur and Tommer Ravid
Biomolecules 2020, 10(8), 1168; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10081168 - 10 Aug 2020
Cited by 9 | Viewed by 2761
Abstract
Intracellular protein inclusions are diverse cellular entities with distinct biological properties. They vary in their protein content, sequestration sites, physiological function, conditions for their generation, and turnover rates. Major distinctions have been recognized between stationary amyloids and dynamic, misfolded protein deposits. The former [...] Read more.
Intracellular protein inclusions are diverse cellular entities with distinct biological properties. They vary in their protein content, sequestration sites, physiological function, conditions for their generation, and turnover rates. Major distinctions have been recognized between stationary amyloids and dynamic, misfolded protein deposits. The former being a dead end for irreversibly misfolded proteins, hence, cleared predominantly by autophagy, while the latter consists of a protein-quality control mechanism, important for cell endurance, where proteins are sequestered during proteotoxic stress and resolved upon its relief. Accordingly, the disaggregation of transient inclusions is a regulated process consisting of protein solubilization, followed by a triage step to either refolding or to ubiquitin-mediated degradation. Recent studies have demonstrated an indispensable role in disaggregation for components of the chaperone and the ubiquitin–proteasome systems. These include heat-shock chaperones of the 40/70/100 kDa families, the proteasome, proteasome substrate shuttling factors, and deubiquitylating enzymes. Thus, a functional link has been established between the chaperone machinery that extracts proteins from transient deposits and 26S proteasome-dependent disaggregation, indicative of a coordinated process. In this review, we discuss data emanating from these important studies and subsequently consolidate the information in the form of a working model for the disaggregation mechanism. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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19 pages, 2069 KiB  
Review
Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism
by Amir Sapir
Biomolecules 2020, 10(8), 1154; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10081154 - 06 Aug 2020
Cited by 8 | Viewed by 3576
Abstract
One of the basic building blocks of all life forms are lipids—biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions [...] Read more.
One of the basic building blocks of all life forms are lipids—biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions and functions of lipids with the physiology of the organism. One type of control on the activity of those enzymes is the conjugation of the Small Ubiquitin-like Modifier (SUMO) that in recent years has been identified as a critical regulator of many biological processes. In this review, I summarize the current knowledge about the role of SUMO in the regulation of lipid metabolism. In particular, I discuss (i) the role of SUMO in lipid metabolism of fungi and invertebrates; (ii) the function of SUMO as a regulator of lipid metabolism in mammals with emphasis on the two most well-characterized cases of SUMO regulation of lipid homeostasis. These include the effect of SUMO on the activity of two groups of master regulators of lipid metabolism—the Sterol Regulatory Element Binding Protein (SERBP) proteins and the family of nuclear receptors—and (iii) the role of SUMO as a regulator of lipid metabolism in arteriosclerosis, nonalcoholic fatty liver, cholestasis, and other lipid-related human diseases. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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24 pages, 1431 KiB  
Review
Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome
by Amanda B. Abildgaard, Sarah K. Gersing, Sven Larsen-Ledet, Sofie V. Nielsen, Amelie Stein, Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen
Biomolecules 2020, 10(8), 1141; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10081141 - 04 Aug 2020
Cited by 21 | Viewed by 5282
Abstract
Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together [...] Read more.
Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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24 pages, 2338 KiB  
Review
Viral Ubiquitin and Ubiquitin-Like Deconjugases—Swiss Army Knives for Infection
by Maria Grazia Masucci
Biomolecules 2020, 10(8), 1137; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10081137 - 01 Aug 2020
Cited by 6 | Viewed by 3470
Abstract
Posttranslational modifications of cellular proteins by covalent conjugation of ubiquitin and ubiquitin-like polypeptides regulate numerous cellular processes that are captured by viruses to promote infection, replication, and spreading. The importance of these protein modifications for the viral life cycle is underscored by the [...] Read more.
Posttranslational modifications of cellular proteins by covalent conjugation of ubiquitin and ubiquitin-like polypeptides regulate numerous cellular processes that are captured by viruses to promote infection, replication, and spreading. The importance of these protein modifications for the viral life cycle is underscored by the discovery that many viruses encode deconjugases that reverse their functions. The structural and functional characterization of these viral enzymes and the identification of their viral and cellular substrates is providing valuable insights into the biology of viral infections and the host’s antiviral defense. Given the growing body of evidence demonstrating their key contribution to pathogenesis, the viral deconjugases are now recognized as attractive targets for the design of novel antiviral therapeutics. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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11 pages, 648 KiB  
Review
The COP9 Signalosome: A Multi-DUB Complex
by Wolfgang Dubiel, Supattra Chaithongyot, Dawadschargal Dubiel and Michael Naumann
Biomolecules 2020, 10(7), 1082; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10071082 - 21 Jul 2020
Cited by 48 | Viewed by 6664
Abstract
The COP9 signalosome (CSN) is a signaling platform controlling the cellular ubiquitylation status. It determines the activity and remodeling of ~700 cullin-RING ubiquitin ligases (CRLs), which control more than 20% of all ubiquitylation events in cells and thereby influence virtually any cellular pathway. [...] Read more.
The COP9 signalosome (CSN) is a signaling platform controlling the cellular ubiquitylation status. It determines the activity and remodeling of ~700 cullin-RING ubiquitin ligases (CRLs), which control more than 20% of all ubiquitylation events in cells and thereby influence virtually any cellular pathway. In addition, it is associated with deubiquitylating enzymes (DUBs) protecting CRLs from autoubiquitylation and rescuing ubiquitylated proteins from degradation. The coordination of ubiquitylation and deubiquitylation by the CSN is presumably important for fine-tuning the precise formation of defined ubiquitin chains. Considering its intrinsic DUB activity specific for deneddylation of CRLs and belonging to the JAMM family as well as its associated DUBs, the CSN represents a multi-DUB complex. Two CSN-associated DUBs, the ubiquitin-specific protease 15 (USP15) and USP48 are regulators in the NF-κB signaling pathway. USP15 protects CRL1β-TrCP responsible for IκBα ubiquitylation, whereas USP48 stabilizes the nuclear pool of the NF-κB transcription factor RelA upon TNF stimulation by counteracting CRL2SOCS1. Moreover, the CSN controls the neddylation status of cells by its intrinsic DUB activity and by destabilizing the associated deneddylation enzyme 1 (DEN1). Thus, the CSN is a master regulator at the intersection between ubiquitylation and neddylation. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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14 pages, 5377 KiB  
Review
Regulation of Interferon Induction by the Ubiquitin-Like Modifier FAT10
by Mei Min Mah, Nicola Roverato and Marcus Groettrup
Biomolecules 2020, 10(6), 951; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10060951 - 23 Jun 2020
Cited by 8 | Viewed by 4197
Abstract
The revelation that the human major histocompatibility complex (MHC) class I locus encodes a ubiquitin-like protein designated HLA-F adjacent transcript 10 (FAT10) or ubiquitin D (UBD) has attracted increasing attention to the function of this protein. Interestingly, the pro-inflammatory cytokines interferon (IFN)-γ and [...] Read more.
The revelation that the human major histocompatibility complex (MHC) class I locus encodes a ubiquitin-like protein designated HLA-F adjacent transcript 10 (FAT10) or ubiquitin D (UBD) has attracted increasing attention to the function of this protein. Interestingly, the pro-inflammatory cytokines interferon (IFN)-γ and tumor necrosis factor (TNF) α synergize to strongly induce FAT10 expression, thereby suggesting a role of FAT10 in the immune response. Recent reports that FAT10 downregulates type I interferon production while it upregulates IFN-γ pose mechanistic questions on how FAT10 differentially regulates interferon induction. Several covalent and non-covalent binding partners of FAT10 involved in signal transduction pathways leading to IFN synthesis have been identified. After introducing FAT10, we review here recent insights into how FAT10 affects proteins in the interferon pathways, like the virus-responsive pattern recognition receptor RIG-I, the ubiquitin ligase ZNF598, and the deubiquitylating enzyme OTUB1. Moreover, we outline the consequences of FAT10 deficiency on interferon synthesis and viral expansion in mice and human cells. We discuss the need for covalent isopeptide linkage of FAT10 to the involved target proteins and the concomitant targeting for proteasomal degradation. After years of investigating the elusive biological functions of this fascinating ubiquitin-like modifier, we review the emerging evidence for a novel role of FAT10 in interferon regulation. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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