Review

23 pages, 5855 KiB

Open AccessReview

by Alexandra Daks, Olga Fedorova, Sergey Parfenyev, Ivan Nevzorov, Oleg Shuvalov and Nickolai A. Barlev

Cells 2022, 11(9), 1515; https://doi.org/10.3390/cells11091515 - 30 Apr 2022

Cited by 6 | Viewed by 2722

Abstract

The p53-dependent ubiquitin ligase Pirh2 regulates a number of proteins involved in different cancer-associated processes. Targeting the p53 family proteins, Chk2, p27^Kip1, Twist1 and others, Pirh2 participates in such cellular processes as proliferation, cell cycle regulation, apoptosis and cellular migration. Thus, [...] Read more.

The p53-dependent ubiquitin ligase Pirh2 regulates a number of proteins involved in different cancer-associated processes. Targeting the p53 family proteins, Chk2, p27^Kip1, Twist1 and others, Pirh2 participates in such cellular processes as proliferation, cell cycle regulation, apoptosis and cellular migration. Thus, it is not surprising that Pirh2 takes part in the initiation and progression of different diseases and pathologies including but not limited to cancer. In this review, we aimed to summarize the available data on Pirh2 regulation, its protein targets and its role in various diseases and pathological processes, thus making the Pirh2 protein a promising therapeutic target. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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Graphical abstract

24 pages, 850 KiB

Open AccessReview

Sumoylation in Physiology, Pathology and Therapy

by Umut Sahin, Hugues de Thé and Valérie Lallemand-Breitenbach

Cells 2022, 11(5), 814; https://doi.org/10.3390/cells11050814 - 26 Feb 2022

Cited by 26 | Viewed by 4843

Abstract

Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the [...] Read more.

Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness. A growing number of prokaryotic and viral proteins are also emerging as prime sumoylation targets, highlighting the role of this modification during infection and in immune processes. Sumoylation also oversees epigenetic processes. Accordingly, at the physiological level, it acts as a crucial regulator of development. Yet, perhaps the most prominent function of sumoylation, from mammals to plants, is its role in orchestrating organismal responses to environmental stresses ranging from hypoxia to nutrient stress. Consequently, a growing list of pathological conditions, including cancer and neurodegeneration, have now been unambiguously associated with either aberrant sumoylation of specific proteins and/or dysregulated global cellular sumoylation. Therapeutic enforcement of sumoylation can also accomplish remarkable clinical responses in various diseases, notably acute promyelocytic leukemia (APL). In this review, we will discuss how this modification is emerging as a novel drug target, highlighting from the perspective of translational medicine, its potential and limitations. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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21 pages, 1187 KiB

Open AccessReview

Deubiquitinases in Neurodegeneration

by Abudu I. Bello, Rituparna Goswami, Shelby L. Brown, Kara Costanzo, Taylor Shores, Shefaa Allan, Revan Odah and Ryan D. Mohan

Cells 2022, 11(3), 556; https://doi.org/10.3390/cells11030556 - 05 Feb 2022

Cited by 13 | Viewed by 3157

Abstract

Ubiquitination refers to the conjugation of the ubiquitin protein (a small protein highly conserved among eukaryotes) to itself or to other proteins through differential use of ubiquitin’s seven internal linkage sites or the amino-terminal amino group. By creating different chain lengths, an enormous [...] Read more.

Ubiquitination refers to the conjugation of the ubiquitin protein (a small protein highly conserved among eukaryotes) to itself or to other proteins through differential use of ubiquitin’s seven internal linkage sites or the amino-terminal amino group. By creating different chain lengths, an enormous proteomic diversity may be formed. This creates a signaling system that is central to controlling almost every conceivable protein function, from proteostasis to regulating enzyme function and everything in between. Protein ubiquitination is reversed through the activity of deubiquitinases (DUBs), enzymes that function to deconjugate ubiquitin from itself and protein substrates. DUBs are regulated through several mechanisms, from controlled subcellular localization within cells to developmental and tissue specific expression. Misregulation of DUBs has been implicated in several diseases including cancer and neurodegeneration. Here we present a brief overview of the role of DUBs in neurodegeneration, and as potential therapeutic targets. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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26 pages, 1216 KiB

Open AccessEditor’s ChoiceReview

ISG15 and ISGylation in Human Diseases

by Oygul Mirzalieva, Meredith Juncker, Joshua Schwartzenburg and Shyamal Desai

Cells 2022, 11(3), 538; https://doi.org/10.3390/cells11030538 - 04 Feb 2022

Cited by 35 | Viewed by 8831

Abstract

Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular [...] Read more.

Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post-translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β-grasp fold in both UBL domains. UBL2 domain has a conserved C-terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN-dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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26 pages, 1668 KiB

Open AccessFeature PaperReview

Killing by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System

by Ruqaia Abbas and Sarit Larisch

Cells 2021, 10(12), 3465; https://doi.org/10.3390/cells10123465 - 08 Dec 2021

Cited by 27 | Viewed by 4989

Abstract

Apoptosis is a cell suicide process that is essential for development, tissue homeostasis and human health. Impaired apoptosis is associated with a variety of human diseases, including neurodegenerative disorders, autoimmunity and cancer. As the levels of pro- and anti-apoptotic proteins can determine the [...] Read more.

Apoptosis is a cell suicide process that is essential for development, tissue homeostasis and human health. Impaired apoptosis is associated with a variety of human diseases, including neurodegenerative disorders, autoimmunity and cancer. As the levels of pro- and anti-apoptotic proteins can determine the life or death of cells, tight regulation of these proteins is critical. The ubiquitin proteasome system (UPS) is essential for maintaining protein turnover, which can either trigger or inhibit apoptosis. In this review, we will describe the E3 ligases that regulate the levels of pro- and anti-apoptotic proteins and assisting proteins that regulate the levels of these E3 ligases. We will provide examples of apoptotic cell death modulations using the UPS, determined by positive and negative feedback loop reactions. Specifically, we will review how the stability of p53, Bcl-2 family members and IAPs (Inhibitor of Apoptosis proteins) are regulated upon initiation of apoptosis. As increased levels of oncogenes and decreased levels of tumor suppressor proteins can promote tumorigenesis, targeting these pathways offers opportunities to develop novel anti-cancer therapies, which act by recruiting the UPS for the effective and selective killing of cancer cells. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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18 pages, 3690 KiB

Open AccessReview

SUMO Interacting Motifs: Structure and Function

by Tak-Yu Yau, William Sander, Christian Eidson and Albert J. Courey

Cells 2021, 10(11), 2825; https://doi.org/10.3390/cells10112825 - 21 Oct 2021

Cited by 32 | Viewed by 6779

Abstract

Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other [...] Read more.

Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid–liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host–pathogen interactions. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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19 pages, 2578 KiB

Open AccessReview

Biochemistry, Pathophysiology, and Regulation of Linear Ubiquitination: Intricate Regulation by Coordinated Functions of the Associated Ligase and Deubiquitinase

by Yasuhiro Fuseya and Kazuhiro Iwai

Cells 2021, 10(10), 2706; https://doi.org/10.3390/cells10102706 - 09 Oct 2021

Cited by 11 | Viewed by 6174

Abstract

The ubiquitin system modulates protein functions by decorating target proteins with ubiquitin chains in most cases. Several types of ubiquitin chains exist, and chain type determines the mode of regulation of conjugated proteins. LUBAC is a ubiquitin ligase complex that specifically generates N-terminally [...] Read more.

The ubiquitin system modulates protein functions by decorating target proteins with ubiquitin chains in most cases. Several types of ubiquitin chains exist, and chain type determines the mode of regulation of conjugated proteins. LUBAC is a ubiquitin ligase complex that specifically generates N-terminally Met1-linked linear ubiquitin chains. Although linear ubiquitin chains are much less abundant than other types of ubiquitin chains, they play pivotal roles in cell survival, proliferation, the immune response, and elimination of bacteria by selective autophagy. Because linear ubiquitin chains regulate inflammatory responses by controlling the proinflammatory transcription factor NF-κB and programmed cell death (including apoptosis and necroptosis), abnormal generation of linear chains can result in pathogenesis. LUBAC consists of HOIP, HOIL-1L, and SHARPIN; HOIP is the catalytic center for linear ubiquitination. LUBAC is unique in that it contains two different ubiquitin ligases, HOIP and HOIL-1L, in the same ligase complex. Furthermore, LUBAC constitutively interacts with the deubiquitinating enzymes (DUBs) OTULIN and CYLD, which cleave linear ubiquitin chains generated by LUBAC. In this review, we summarize the current status of linear ubiquitination research, and we discuss the intricate regulation of LUBAC-mediated linear ubiquitination by coordinate function of the HOIP and HOIL-1L ligases and OTULIN. Furthermore, we discuss therapeutic approaches to targeting LUBAC-mediated linear ubiquitin chains. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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22 pages, 2527 KiB

Open AccessReview

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma

by Cristian Prieto-Garcia, Ines Tomašković, Varun Jayeshkumar Shah, Ivan Dikic and Markus Diefenbacher

Cells 2021, 10(10), 2652; https://doi.org/10.3390/cells10102652 - 04 Oct 2021

Cited by 16 | Viewed by 4911

Abstract

Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential [...] Read more.

Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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17 pages, 1354 KiB

Open AccessFeature PaperReview

From the Evasion of Degradation to Ubiquitin-Dependent Protein Stabilization

by Yamen Abu Ahmad, Avital Oknin-Vaisman, Eliya Bitman-Lotan and Amir Orian

Cells 2021, 10(9), 2374; https://doi.org/10.3390/cells10092374 - 09 Sep 2021

Cited by 14 | Viewed by 3893

Abstract

A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by [...] Read more.

A hallmark of cancer is dysregulated protein turnover (proteostasis), which involves pathologic ubiquitin-dependent degradation of tumor suppressor proteins, as well as increased oncoprotein stabilization. The latter is due, in part, to mutation within sequences, termed degrons, which are required for oncoprotein recognition by the substrate-recognition enzyme, E3 ubiquitin ligase. Stabilization may also result from the inactivation of the enzymatic machinery that mediates the degradation of oncoproteins. Importantly, inactivation in cancer of E3 enzymes that regulates the physiological degradation of oncoproteins, results in tumor cells that accumulate multiple active oncoproteins with prolonged half-lives, leading to the development of “degradation-resistant” cancer cells. In addition, specific sequences may enable ubiquitinated proteins to evade degradation at the 26S proteasome. While the ubiquitin-proteasome pathway was originally discovered as central for protein degradation, in cancer cells a ubiquitin-dependent protein stabilization pathway actively translates transient mitogenic signals into long-lasting protein stabilization and enhances the activity of key oncoproteins. A central enzyme in this pathway is the ubiquitin ligase RNF4. An intimate link connects protein stabilization with tumorigenesis in experimental models as well as in the clinic, suggesting that pharmacological inhibition of protein stabilization has potential for personalized medicine in cancer. In this review, we highlight old observations and recent advances in our knowledge regarding protein stabilization. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Pathways in Development and Disease)

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