scholarly journals Up-regulation of ubiquitin–proteasome activity upon loss of NatA-dependent N-terminal acetylation

2021 ◽  
Vol 5 (2) ◽  
pp. e202000730
Author(s):  
Ilia Kats ◽  
Christian Reinbold ◽  
Marc Kschonsak ◽  
Anton Khmelinskii ◽  
Laura Armbruster ◽  
...  
Keyword(s):  
Protein Stability ◽  
Protein Modification ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Protein Homeostasis ◽  
Master Regulator ◽  
E3 Ligases ◽  
System Activity ◽  
Proteasomal Genes ◽  
Ubiquitin Proteasome

N-terminal acetylation is a prominent protein modification, and inactivation of N-terminal acetyltransferases (NATs) cause protein homeostasis stress. Using multiplexed protein stability profiling with linear ubiquitin fusions as reporters for the activity of the ubiquitin proteasome system, we observed increased ubiquitin proteasome system activity in NatA, but not NatB or NatC mutants. We find several mechanisms contributing to this behavior. First, NatA-mediated acetylation of the N-terminal ubiquitin–independent degron regulates the abundance of Rpn4, the master regulator of the expression of proteasomal genes. Second, the abundance of several E3 ligases involved in degradation of UFD substrates is increased in cells lacking NatA. Finally, we identify the E3 ligase Tom1 as a novel chain-elongating enzyme (E4) involved in the degradation of linear ubiquitin fusions via the formation of branched K11, K29, and K48 ubiquitin chains, independently of the known E4 ligases involved in UFD, leading to enhanced ubiquitination of the UFD substrates.

scholarly journals Mechanisms of up-regulation of Ubiquitin-Proteasome activity in the absence of NatA dependent N-terminal acetylation

2020 ◽  
Author(s):  
Ilia Kats ◽  
Marc Kschonsak ◽  
Anton Khmelinskii ◽  
Laura Armbruster ◽  
Thomas Ruppert ◽  
...  
Keyword(s):  
Protein Stability ◽  
Protein Modification ◽  
E3 Ligase ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Protein Homeostasis ◽  
Master Regulator ◽  
E3 Ligases ◽  
Proteasomal Genes ◽  
Ubiquitin Proteasome

AbstractN-terminal acetylation is a prominent protein modification and inactivation of N-terminal acetyltransferases (NATs) cause protein homeostasis stress. Using multiplexed protein stability (MPS) profiling with linear ubiquitin fusions as reporters for the activity of the ubiquitin proteasome system (UPS) we observed increased UPS activity in NatA, but not NatB or NatC mutants. We find several mechanisms contributing to this behavior. First, NatA-mediated acetylation of the N-terminal ubiquitin independent degron regulates the abundance of Rpn4, the master regulator of the expression of proteasomal genes. Second, the abundance of several E3 ligases involved in degradation of UFD substrates is increased in cells lacking NatA. Finally, we identify the E3 ligase Tom1 as a novel chain elongating enzyme (E4) involved in the degradation of linear ubiquitin fusions via the formation of branched K11 and K29 ubiquitin chains, independently of the known E4 ligases involved in UFD, leading to enhanced ubiquitination of the UFD substrates.

scholarly journals Tuning the proteasome to brighten the end of the journey

2016 ◽  
Vol 311 (5) ◽  
pp. C793-C804 ◽  
Author(s):  
Thibault Mayor ◽  
Michal Sharon ◽  
Michael H. Glickman
Keyword(s):  
Cell Cycle Progression ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Cellular Proteins ◽  
Regulatory Mechanisms ◽  
Protein Homeostasis ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Age Related ◽  
Ubiquitin Proteasome

Degradation by the proteasome is the fate for a large portion of cellular proteins, and it plays a major role in maintaining protein homeostasis, as well as in regulating many cellular processes like cell cycle progression. A decrease in proteasome activity has been linked to aging and several age-related neurodegenerative pathologies and highlights the importance of the ubiquitin proteasome system regulation. While the proteasome has been traditionally viewed as a constitutive element of proteolysis, major studies have highlighted how different regulatory mechanisms can impact its activity. Importantly, alterations of proteasomal activity may have major impacts for its function and in therapeutics. On one hand, increasing proteasome activity could be beneficial to prevent the age-related downfall of protein homeostasis, whereas inhibiting or reducing its activity can prevent the proliferation of cancer cells.

scholarly journals Immunoproteasome Function in Normal and Malignant Hematopoiesis

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1577
Author(s):  
Nuria Tubío-Santamaría ◽  
Frédéric Ebstein ◽  
Florian H. Heidel ◽  
Elke Krüger
Keyword(s):  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Protein Homeostasis ◽  
Efficacy And Safety ◽  
Hematopoietic System ◽  
Oxidized Proteins ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Early Phases

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

scholarly journals Cullin Deneddylation Suppresses the Necroptotic Pathway in Cardiomyocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Megan T. Lewno ◽  
Taixing Cui ◽  
Xuejun Wang
Keyword(s):  
Ubiquitin Proteasome System ◽  
Arrhythmogenic Right Ventricular Dysplasia ◽  
Cop9 Signalosome ◽  
E3 Ligases ◽  
Protein Subunits ◽  
Unique Protein ◽  
Recent Advances ◽  
Regulated Necrosis ◽  
Ubiquitin Proteasome ◽  
Apoptosis And Necrosis

Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin–proteasome system (UPS) but also the autophagic–lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1–RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

scholarly journals Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

scholarly journals The Ubiquitin Proteasome System in Ischemic and Dilated Cardiomyopathy

2019 ◽  
Vol 20 (24) ◽  
pp. 6354 ◽  
Author(s):  
Sabine Spänig ◽  
Kristina Kellermann ◽  
Maja-Theresa Dieterlen ◽  
Thilo Noack ◽  
Sven Lehmann ◽  
...  
Keyword(s):  
Protein Expression ◽  
Ubiquitin Proteasome System ◽  
Translation Initiation Factor ◽  
Myocardial Tissue ◽  
Activation Markers ◽  
E3 Ligases ◽  
Proteasomal Activity ◽  
Ubiquitin Proteasome ◽  
Statistical Trends ◽  
And Control

Dilated (DCM) and ischemic cardiomyopathies (ICM) are associated with cardiac remodeling, where the ubiquitin–proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. The aim of this study is to characterize the UPS activity in human heart tissue from cardiomyopathy patients. Myocardial tissue from ICM (n = 23), DCM (n = 28), and control (n = 14) patients were used to quantify ubiquitinylated proteins, E3-ubiquitin-ligases muscle-atrophy-F-box (MAFbx)/atrogin-1, muscle-RING-finger-1 (MuRF1), and eukaryotic-translation-initiation-factor-4E (eIF4E), by Western blot. Furthermore, the proteasomal chymotrypsin-like and trypsin-like peptidase activities were determined fluorometrically. Enzyme activity of NAD(P)H oxidase was assessed as an index of reactive oxygen species production. The chymotrypsin- (p = 0.71) and caspase-like proteasomal activity (p = 0.93) was similar between the groups. Trypsin-like proteasomal activity was lower in ICM (0.78 ± 0.11 µU/mg) compared to DCM (1.06 ± 0.08 µU/mg) and control (1.00 ± 0.06 µU/mg; p = 0.06) samples. Decreased ubiquitin expression in both cardiomyopathy groups (ICM vs. control: p < 0.001; DCM vs. control: p < 0.001), as well as less ubiquitin-positive deposits in ICM-damaged tissue (ICM: 4.19% ± 0.60%, control: 6.28% ± 0.40%, p = 0.022), were detected. E3-ligase MuRF1 protein expression (p = 0.62), NADPH-oxidase activity (p = 0.63), and AIF-positive cells (p = 0.50). Statistical trends were detected for reduced MAFbx protein expression in the DCM-group (p = 0.07). Different levels of UPS components, E3 ligases, and UPS activation markers were observed in myocardial tissue from patients affected by DCM and ICM, suggesting differential involvement of the UPS in the underlying pathologies.

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Xiaowei Wu ◽  
Qingyu Luo ◽  
Zhihua Liu
Keyword(s):  
Clinical Practice ◽  
Cancer Cells ◽  
Therapeutic Target ◽  
Crucial Role ◽  
Ubiquitin Proteasome System ◽  
Therapeutic Strategies ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Specific Inhibitors

Abstract MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination-mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin–proteasome system in clinical practice.

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