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15 pages, 3117 KiB

Open AccessArticle

Semisynthetic Modification of Tau Protein with Di-Ubiquitin Chains for Aggregation Studies

by Francesca Munari, Carlo Giorgio Barracchia, Francesca Parolini, Roberto Tira, Luigi Bubacco, Michael Assfalg and Mariapina D’Onofrio

Int. J. Mol. Sci. 2020, 21(12), 4400; https://doi.org/10.3390/ijms21124400 - 20 Jun 2020

Cited by 20 | Viewed by 2947

Abstract

Ubiquitin, a protein modifier that regulates diverse essential cellular processes, is also a component of the protein inclusions characteristic of many neurodegenerative disorders. In Alzheimer’s disease, the microtubule associated tau protein accumulates within damaged neurons in the form of cross-beta structured filaments. Both [...] Read more.

Ubiquitin, a protein modifier that regulates diverse essential cellular processes, is also a component of the protein inclusions characteristic of many neurodegenerative disorders. In Alzheimer’s disease, the microtubule associated tau protein accumulates within damaged neurons in the form of cross-beta structured filaments. Both mono- and polyubiquitin were found linked to several lysine residues belonging to the region of tau protein that forms the structured core of the filaments. Thus, besides priming the substrate protein for proteasomal degradation, ubiquitin could also contribute to the assembly and stabilization of tau protein filaments. To advance our understanding of the impact of ubiquitination on tau protein aggregation and function, we applied disulfide-coupling chemistry to modify tau protein at position 353 with Lys48- or Lys63-linked di-ubiquitin, two representative polyubiquitin chains that differ in topology and structure. Aggregation kinetics experiments performed on these conjugates reveal that di-ubiquitination retards filament formation and perturbs the fibril elongation rate more than mono-ubiquitination. We further show that di-ubiquitination modulates tau-mediated microtubule assembly. The effects on tau protein aggregation and microtubule polymerization are essentially independent from polyubiquitin chain topology. Altogether, our findings provide novel insight into the consequences of ubiquitination on the functional activity and disease-related behavior of tau protein. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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Review

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24 pages, 2105 KiB

Open AccessReview

The Effect of Dysfunctional Ubiquitin Enzymes in the Pathogenesis of Most Common Diseases

by Gizem Celebi, Hale Kesim, Ebru Ozer and Ozlem Kutlu

Int. J. Mol. Sci. 2020, 21(17), 6335; https://doi.org/10.3390/ijms21176335 - 01 Sep 2020

Cited by 29 | Viewed by 5349

Abstract

Ubiquitination is a multi-step enzymatic process that involves the marking of a substrate protein by bonding a ubiquitin and protein for proteolytic degradation mainly via the ubiquitin–proteasome system (UPS). The process is regulated by three main types of enzymes, namely ubiquitin-activating enzymes (E1), [...] Read more.

Ubiquitination is a multi-step enzymatic process that involves the marking of a substrate protein by bonding a ubiquitin and protein for proteolytic degradation mainly via the ubiquitin–proteasome system (UPS). The process is regulated by three main types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). Under physiological conditions, ubiquitination is highly reversible reaction, and deubiquitinases or deubiquitinating enzymes (DUBs) can reverse the effect of E3 ligases by the removal of ubiquitin from substrate proteins, thus maintaining the protein quality control and homeostasis in the cell. The dysfunction or dysregulation of these multi-step reactions is closely related to pathogenic conditions; therefore, understanding the role of ubiquitination in diseases is highly valuable for therapeutic approaches. In this review, we first provide an overview of the molecular mechanism of ubiquitination and UPS; then, we attempt to summarize the most common diseases affecting the dysfunction or dysregulation of these mechanisms. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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21 pages, 1162 KiB

Open AccessReview

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

by Takashi Shiromizu, Mizuki Yuge, Kousuke Kasahara, Daishi Yamakawa, Takaaki Matsui, Yasumasa Bessho, Masaki Inagaki and Yuhei Nishimura

Int. J. Mol. Sci. 2020, 21(17), 5962; https://doi.org/10.3390/ijms21175962 - 19 Aug 2020

Cited by 10 | Viewed by 3485

Abstract

Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause [...] Read more.

Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function. The structure and function of cilia are dynamically regulated through various mechanisms, among which E3 ubiquitin ligases and deubiquitinases play crucial roles. These enzymes regulate the degradation and stabilization of ciliary proteins through the ubiquitin–proteasome system. In this review, we briefly highlight the role of cilia in ciliopathy and cancer; describe the roles of E3 ubiquitin ligases and deubiquitinases in ciliogenesis, ciliopathy, and cancer; and highlight some of the E3 ubiquitin ligases and deubiquitinases that are potential therapeutic targets for these disorders. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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12 pages, 555 KiB

Open AccessReview

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review

by Osamu Yamazaki, Daigoro Hirohama, Kenichi Ishizawa and Shigeru Shibata

Int. J. Mol. Sci. 2020, 21(15), 5358; https://doi.org/10.3390/ijms21155358 - 28 Jul 2020

Cited by 9 | Viewed by 3186

Abstract

The kidney and the vasculature play crucial roles in regulating blood pressure. The ubiquitin proteasome system (UPS), a multienzyme process mediating covalent conjugation of the 76-amino acid polypeptide ubiquitin to a substrate protein followed by proteasomal degradation, is involved in multiple cellular processes [...] Read more.

The kidney and the vasculature play crucial roles in regulating blood pressure. The ubiquitin proteasome system (UPS), a multienzyme process mediating covalent conjugation of the 76-amino acid polypeptide ubiquitin to a substrate protein followed by proteasomal degradation, is involved in multiple cellular processes by regulating protein turnover in various tissues. Increasing evidence demonstrates the roles of UPS in blood pressure regulation. In the kidney, filtered sodium is reabsorbed through diverse sodium transporters and channels along renal tubules, and studies conducted till date have provided insights into the complex molecular network through which ubiquitin ligases modulate sodium transport in different segments. Components of these pathways include ubiquitin ligase neuronal precursor cell-expressed developmentally downregulated 4-2, Cullin-3, and Kelch-like 3. Moreover, accumulating data indicate the roles of UPS in blood vessels, where it modulates nitric oxide bioavailability and vasoconstriction. Cullin-3 not only regulates renal salt reabsorption but also controls vascular tone using different adaptor proteins that target distinct substrates in vascular smooth muscle cells. In endothelial cells, UPS can also contribute to blood pressure regulation by modulating endothelial nitric oxide synthase. In this review, we summarize current knowledge regarding the role of UPS in blood pressure regulation, focusing on renal sodium reabsorption and vascular function. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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13 pages, 645 KiB

Open AccessReview

The Regulatory Role of T Cell Responses in Cardiac Remodeling Following Myocardial Infarction

by Tabito Kino, Mohsin Khan and Sadia Mohsin

Int. J. Mol. Sci. 2020, 21(14), 5013; https://doi.org/10.3390/ijms21145013 - 16 Jul 2020

Cited by 24 | Viewed by 3650

Abstract

Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adverse remodeling and formation of scar tissue at the site of injury. The dying cardiac tissue secretes a variety of cytokines and chemokines that trigger an inflammatory response and [...] Read more.

Ischemic injury to the heart causes cardiomyocyte and supportive tissue death that result in adverse remodeling and formation of scar tissue at the site of injury. The dying cardiac tissue secretes a variety of cytokines and chemokines that trigger an inflammatory response and elicit the recruitment and activation of cardiac immune cells to the injury site. Cell-based therapies for cardiac repair have enhanced cardiac function in the injured myocardium, but the mechanisms remain debatable. In this review, we will focus on the interactions between the adoptively transferred stem cells and the post-ischemic environment, including the active components of the immune/inflammatory response that can mediate cardiac outcome after ischemic injury. In particular, we highlight how the adaptive immune cell response can mediate tissue repair following cardiac injury. Several cell-based studies have reported an increase in pro-reparative T cell subsets after stem cell transplantation. Paracrine factors secreted by stem cells polarize T cell subsets partially by exogenous ubiquitination, which can induce differentiation of T cell subset to promote tissue repair after myocardial infarction (MI). However, the mechanism behind the polarization of different subset after stem cell transplantation remains poorly understood. In this review, we will summarize the current status of immune cells within the heart post-MI with an emphasis on T cell mediated reparative response after ischemic injury. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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23 pages, 1230 KiB

Open AccessReview

Protein Degradation and the Pathologic Basis of Phenylketonuria and Hereditary Tyrosinemia

by Neha Sarodaya, Bharathi Suresh, Kye-Seong Kim and Suresh Ramakrishna

Int. J. Mol. Sci. 2020, 21(14), 4996; https://doi.org/10.3390/ijms21144996 - 15 Jul 2020

Cited by 6 | Viewed by 7074

Abstract

A delicate intracellular balance among protein synthesis, folding, and degradation is essential to maintaining protein homeostasis or proteostasis, and it is challenged by genetic and environmental factors. Molecular chaperones and the ubiquitin proteasome system (UPS) play a vital role in proteostasis for normal [...] Read more.

A delicate intracellular balance among protein synthesis, folding, and degradation is essential to maintaining protein homeostasis or proteostasis, and it is challenged by genetic and environmental factors. Molecular chaperones and the ubiquitin proteasome system (UPS) play a vital role in proteostasis for normal cellular function. As part of protein quality control, molecular chaperones recognize misfolded proteins and assist in their refolding. Proteins that are beyond repair or refolding undergo degradation, which is largely mediated by the UPS. The importance of protein quality control is becoming ever clearer, but it can also be a disease-causing mechanism. Diseases such as phenylketonuria (PKU) and hereditary tyrosinemia-I (HT1) are caused due to mutations in PAH and FAH gene, resulting in reduced protein stability, misfolding, accelerated degradation, and deficiency in functional proteins. Misfolded or partially unfolded proteins do not necessarily lose their functional activity completely. Thus, partially functional proteins can be rescued from degradation by molecular chaperones and deubiquitinating enzymes (DUBs). Deubiquitination is an important mechanism of the UPS that can reverse the degradation of a substrate protein by covalently removing its attached ubiquitin molecule. In this review, we discuss the importance of molecular chaperones and DUBs in reducing the severity of PKU and HT1 by stabilizing and rescuing mutant proteins. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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19 pages, 15029 KiB

Open AccessReview

Specificity in Ubiquitination Triggered by Virus Infection

by Haidong Gu and Behdokht Jan Fada

Int. J. Mol. Sci. 2020, 21(11), 4088; https://doi.org/10.3390/ijms21114088 - 08 Jun 2020

Cited by 33 | Viewed by 5272

Abstract

Ubiquitination is a prominent posttranslational modification, in which the ubiquitin moiety is covalently attached to a target protein to influence protein stability, interaction partner and biological function. All seven lysine residues of ubiquitin, along with the N-terminal methionine, can each serve as a [...] Read more.

Ubiquitination is a prominent posttranslational modification, in which the ubiquitin moiety is covalently attached to a target protein to influence protein stability, interaction partner and biological function. All seven lysine residues of ubiquitin, along with the N-terminal methionine, can each serve as a substrate for further ubiquitination, which effectuates a diverse combination of mono- or poly-ubiquitinated proteins with linear or branched ubiquitin chains. The intricately composed ubiquitin codes are then recognized by a large variety of ubiquitin binding domain (UBD)-containing proteins to participate in the regulation of various pathways to modulate the cell behavior. Viruses, as obligate parasites, involve many aspects of the cell pathways to overcome host defenses and subjugate cellular machineries. In the virus-host interactions, both the virus and the host tap into the rich source of versatile ubiquitination code in order to compete, combat, and co-evolve. Here, we review the recent literature to discuss the role of ubiquitin system as the infection progresses in virus life cycle and the importance of ubiquitin specificity in the regulation of virus-host relation. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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16 pages, 1120 KiB

Open AccessReview

The Role of Tissue-Specific Ubiquitin Ligases, RNF183, RNF186, RNF182 and RNF152, in Disease and Biological Function

by Takumi Okamoto, Kazunori Imaizumi and Masayuki Kaneko

Int. J. Mol. Sci. 2020, 21(11), 3921; https://doi.org/10.3390/ijms21113921 - 30 May 2020

Cited by 29 | Viewed by 4429

Abstract

Ubiquitylation plays multiple roles not only in proteasome-mediated protein degradation but also in various other cellular processes including DNA repair, signal transduction, and endocytosis. Ubiquitylation is mediated by ubiquitin ligases, which are predicted to be encoded by more than 600 genes in humans. [...] Read more.

Ubiquitylation plays multiple roles not only in proteasome-mediated protein degradation but also in various other cellular processes including DNA repair, signal transduction, and endocytosis. Ubiquitylation is mediated by ubiquitin ligases, which are predicted to be encoded by more than 600 genes in humans. RING finger (RNF) proteins form the majority of these ubiquitin ligases. It has also been predicted that there are 49 RNF proteins containing transmembrane regions in humans, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways. Of these, RNF183, RNF186, RNF182, and RNF152 are closely related genes with high homology. These genes share a unique common feature of exhibiting tissue-specific expression patterns, such as in the kidney, nervous system, and colon. The products of these genes are also reported to be involved in various diseases such as cancers, inflammatory bowel disease, Alzheimer’s disease, and chronic kidney disease, and in various biological functions such as apoptosis, endoplasmic reticulum stress, osmotic stress, nuclear factor-kappa B (NF-κB), mammalian target of rapamycin (mTOR), and Notch signaling. This review summarizes the current knowledge of these tissue-specific ubiquitin ligases, focusing on their physiological roles and significance in diseases. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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13 pages, 1124 KiB

Open AccessReview

Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension

by Tomoaki Ishigami, Tabito Kino, Shintaro Minegishi, Naomi Araki, Masanari Umemura, Hisako Ushio, Sae Saigoh and Michiko Sugiyama

Int. J. Mol. Sci. 2020, 21(11), 3871; https://doi.org/10.3390/ijms21113871 - 29 May 2020

Cited by 8 | Viewed by 3784

Abstract

Ubiquitination is a representative, reversible biological process of the post-translational modification of various proteins with multiple catalytic reaction sequences, including ubiquitin itself, in addition to E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, E3 ubiquitin ligase, deubiquitinating enzymes, and proteasome degradation. The ubiquitin–proteasome [...] Read more.

Ubiquitination is a representative, reversible biological process of the post-translational modification of various proteins with multiple catalytic reaction sequences, including ubiquitin itself, in addition to E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, E3 ubiquitin ligase, deubiquitinating enzymes, and proteasome degradation. The ubiquitin–proteasome system is known to play a pivotal role in various molecular life phenomena, including the cell cycle, protein quality, and cell surface expressions of ion-transporters. As such, the failure of this system can lead to cancer, neurodegenerative diseases, cardiovascular diseases, and hypertension. This review article discusses Nedd4-2/NEDD4L, an E3-ubiquitin ligase involved in salt-sensitive hypertension, drawing from detailed genetic dissection analysis and the development of genetically engineered mice model. Based on our analyses, targeting therapeutic regulations of ubiquitination in the fields of cardio-vascular medicine might be a promising strategy in future. Although the clinical applications of this strategy are limited, compared to those of kinase systems, many compounds with a high pharmacological activity were identified at the basic research level. Therefore, future development could be expected. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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13 pages, 1626 KiB

Open AccessReview

Overview of Mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5 from Molecular Mechanisms to Diseases

by Isshin Shiiba, Keisuke Takeda, Shun Nagashima and Shigeru Yanagi

Int. J. Mol. Sci. 2020, 21(11), 3781; https://doi.org/10.3390/ijms21113781 - 27 May 2020

Cited by 20 | Viewed by 4983

Abstract

The molecular pathology of diseases seen from the mitochondrial axis has become more complex with the progression of research. A variety of factors, including the failure of mitochondrial dynamics and quality control, have made it extremely difficult to narrow down drug discovery targets. [...] Read more.

The molecular pathology of diseases seen from the mitochondrial axis has become more complex with the progression of research. A variety of factors, including the failure of mitochondrial dynamics and quality control, have made it extremely difficult to narrow down drug discovery targets. We have identified MITOL (mitochondrial ubiquitin ligase: also known as MARCH5) localized on the mitochondrial outer membrane and previously reported that it is an important regulator of mitochondrial dynamics and mitochondrial quality control. In this review, we describe the pathological aspects of MITOL revealed through functional analysis and its potential as a drug discovery target. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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19 pages, 2750 KiB

Open AccessReview

Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia

by Ichiro Kawahata and Kohji Fukunaga

Int. J. Mol. Sci. 2020, 21(11), 3779; https://doi.org/10.3390/ijms21113779 - 27 May 2020

Cited by 40 | Viewed by 9513

Abstract

Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine [...] Read more.

Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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24 pages, 3355 KiB

Open AccessReview

Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders

by Daisuke Oikawa, Yusuke Sato, Hidefumi Ito and Fuminori Tokunaga

Int. J. Mol. Sci. 2020, 21(9), 3381; https://doi.org/10.3390/ijms21093381 - 11 May 2020

Cited by 35 | Viewed by 6976

Abstract

The linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin ligase composed of the Heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein (HOIP), and Shank-associated RH domain interactor (SHARPIN) subunits. LUBAC specifically generates the N-terminal Met1-linked linear ubiquitin chain and regulates acquired and innate [...] Read more.

The linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin ligase composed of the Heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein (HOIP), and Shank-associated RH domain interactor (SHARPIN) subunits. LUBAC specifically generates the N-terminal Met1-linked linear ubiquitin chain and regulates acquired and innate immune responses, such as the canonical nuclear factor-κB (NF-κB) and interferon antiviral pathways. Deubiquitinating enzymes, OTULIN and CYLD, physiologically bind to HOIP and control its function by hydrolyzing the linear ubiquitin chain. Moreover, proteins containing linear ubiquitin-specific binding domains, such as NF-κB-essential modulator (NEMO), optineurin, A20-binding inhibitors of NF-κB (ABINs), and A20, modulate the functions of LUBAC, and the dysregulation of the LUBAC-mediated linear ubiquitination pathway induces cancer and inflammatory, autoimmune, and neurodegenerative diseases. Therefore, inhibitors of LUBAC would be valuable to facilitate investigations of the molecular and cellular bases for LUBAC-mediated linear ubiquitination and signal transduction, and for potential therapeutic purposes. We identified and characterized α,β-unsaturated carbonyl-containing chemicals, named HOIPINs (HOIP inhibitors), as LUBAC inhibitors. We summarize recent advances in elucidations of the pathophysiological functions of LUBAC-mediated linear ubiquitination and identifications of its regulators, toward the development of LUBAC inhibitors. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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18 pages, 732 KiB

Open AccessReview

Cracking the Monoubiquitin Code of Genetic Diseases

by Raj Nayan Sewduth, Maria Francesca Baietti and Anna A. Sablina

Int. J. Mol. Sci. 2020, 21(9), 3036; https://doi.org/10.3390/ijms21093036 - 25 Apr 2020

Cited by 16 | Viewed by 4961

Abstract

Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent [...] Read more.

Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent studies uncovered the role of single ubiquitin modification in important physiological processes. Monoubiquitination can modulate the stability, subcellular localization, binding properties, and activity of the target proteins. Understanding the function of monoubiquitination in normal physiology and pathology has important therapeutic implications, as alterations in the monoubiquitin pathway are found in a broad range of genetic diseases. This review highlights a link between monoubiquitin signaling and the pathogenesis of genetic disorders. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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15 pages, 1617 KiB

Open AccessReview

Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

by Amanda Fiore, Yue Liang, Yun Hsiao Lin, Jacky Tung, HanChen Wang, David Langlais and Anastasia Nijnik

Int. J. Mol. Sci. 2020, 21(8), 3007; https://doi.org/10.3390/ijms21083007 - 24 Apr 2020

Cited by 21 | Viewed by 4413

Abstract

MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes [...] Read more.

MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes to the nucleus, where it can interact with chromatin and regulate gene expression, through deubiquitination of histone H2A and non-catalytic contacts with other transcriptional regulators. A cytosolic form of MYSM1 protein was also recently described and demonstrated to regulate signal transduction pathways of innate immunity, by promoting the deubiquitination of TRAF3, TRAF6, and RIP2. In this work we review the current knowledge on the molecular mechanisms of action of MYSM1 protein in transcriptional regulation, signal transduction, and potentially other cellular processes. The functions of MYSM1 in different cell types and aspects of mammalian physiology are also reviewed, highlighting the key checkpoints in hematopoiesis, immunity, and beyond regulated by MYSM1. Importantly, mutations in MYSM1 in human were recently linked to a rare hereditary disorder characterized by leukopenia, anemia, and other hematopoietic and developmental abnormalities. Our growing knowledge of MYSM1 functions and mechanisms of actions sheds important insights into its role in mammalian physiology and the etiology of the MYSM1-deficiency disorder in human. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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22 pages, 906 KiB

Open AccessReview

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

by Keng Po Lai, Jian Chen and William Ka Fai Tse

Int. J. Mol. Sci. 2020, 21(7), 2548; https://doi.org/10.3390/ijms21072548 - 06 Apr 2020

Cited by 32 | Viewed by 4711

Abstract

Deubiquitinases (DUBs) are involved in various cellular functions. They deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. Studies on the roles of deubiquitylation have been conducted in various cancers to identify the carcinogenic roles of DUBs. In this review, [...] Read more.

Deubiquitinases (DUBs) are involved in various cellular functions. They deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. Studies on the roles of deubiquitylation have been conducted in various cancers to identify the carcinogenic roles of DUBs. In this review, we evaluate the biological roles of DUBs in cancer, including proliferation, cell cycle control, apoptosis, the DNA damage response, tumor suppression, oncogenesis, and metastasis. This review mainly focuses on the regulation of different downstream effectors and pathways via biochemical regulation and posttranslational modifications. We summarize the relationship between DUBs and human cancers and discuss the potential of DUBs as therapeutic targets for cancer treatment. This review also provides basic knowledge of DUBs in the development of cancers and highlights the importance of DUBs in cancer biology. Full article

(This article belongs to the Special Issue Ubiquitination in Health and Diseases)

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