scholarly journals The ubiquitin proteasome system and myocardial ischemia

2013 ◽  
Vol 304 (3) ◽  
pp. H337-H349 ◽  
Author(s):  
Justine Calise ◽  
Saul R. Powell
Keyword(s):  
Myocardial Ischemia ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Future Directions ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome ◽  
The Subject ◽  
Idiopathic Cardiomyopathies ◽  
Ubiquitination Machinery

The ubiquitin proteasome system (UPS) has been the subject of intensive research over the past 20 years to define its role in normal physiology and in pathophysiology. Many of these studies have focused in on the cardiovascular system and have determined that the UPS becomes dysfunctional in several pathologies such as familial and idiopathic cardiomyopathies, atherosclerosis, and myocardial ischemia. This review presents a synopsis of the literature as it relates to the role of the UPS in myocardial ischemia. Studies have shown that the UPS is dysfunctional during myocardial ischemia, and recent studies have shed some light on possible mechanisms. Other studies have defined a role for the UPS in ischemic preconditioning which is best associated with myocardial ischemia and is thus presented here. Very recent studies have started to define roles for specific proteasome subunits and components of the ubiquitination machinery in various aspects of myocardial ischemia. Lastly, despite the evidence linking myocardial ischemia and proteasome dysfunction, there are continuing suggestions that proteasome inhibitors may be useful to mitigate ischemic injury. This review presents the rationale behind this and discusses both supportive and nonsupportive studies and presents possible future directions that may help in clarifying this controversy.

scholarly journals Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Frédéric Ebstein ◽  
Sébastien Küry ◽  
Jonas Johannes Papendorf ◽  
Elke Krüger
Keyword(s):  
Neurodevelopmental Disorders ◽  
Ubiquitin Proteasome System ◽  
Immune Dysregulation ◽  
Innate Immune ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome ◽  
E2 Enzymes ◽  
Novel Therapeutic Strategies ◽  
The Brain

Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

scholarly journals Inhibition of the Ubiquitin-Proteasome System Prevents Vaccinia Virus DNA Replication and Expression of Intermediate and Late Genes

2009 ◽  
Vol 83 (6) ◽  
pp. 2469-2479 ◽  
Author(s):  
P. S. Satheshkumar ◽  
Luis C. Anton ◽  
Patrick Sanz ◽  
Bernard Moss
Keyword(s):  
Gene Expression ◽  
Vaccinia Virus ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Late Gene ◽  
Late Gene Expression ◽  
Viral Dna ◽  
Late Genes ◽  
Ubiquitin Proteasome

ABSTRACT The ubiquitin-proteasome system has a central role in the degradation of intracellular proteins and regulates a variety of functions. Viruses belonging to several different families utilize or modulate the system for their advantage. Here we showed that the proteasome inhibitors MG132 and epoxomicin blocked a postentry step in vaccinia virus (VACV) replication. When proteasome inhibitors were added after virus attachment, early gene expression was prolonged and the expression of intermediate and late genes was almost undetectable. By varying the time of the removal and addition of MG132, the adverse effect of the proteasome inhibitors was narrowly focused on events occurring 2 to 4 h after infection, the time of the onset of viral DNA synthesis. Further analyses confirmed that genome replication was inhibited by both MG132 and epoxomicin, which would account for the effect on intermediate and late gene expression. The virus-induced replication of a transfected plasmid was also inhibited, indicating that the block was not at the step of viral DNA uncoating. UBEI-41, an inhibitor of the ubiquitin-activating enzyme E1, also prevented late gene expression, supporting the role of the ubiquitin-proteasome system in VACV replication. Neither the overexpression of ubiquitin nor the addition of an autophagy inhibitor was able to counter the inhibitory effects of MG132. Further studies of the role of the ubiquitin-proteasome system for VACV replication may provide new insights into virus-host interactions and suggest potential antipoxviral drugs.

scholarly journals The Capture of a Disabled Proteasome Identifies Erg25 as a Substrate for Endoplasmic Reticulum Associated Degradation

2020 ◽  
Vol 19 (11) ◽  
pp. 1896-1909
Author(s):  
Teresa M. Buck ◽  
Xuemei Zeng ◽  
Pamela S. Cantrell ◽  
Richard T. Cattley ◽  
Zikri Hasanbasri ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ubiquitin Proteasome System ◽  
Sterol Synthesis ◽  
High Confidence ◽  
Assembly Pathway ◽  
Affinity Isolation ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome ◽  
Erad Pathway

Studies in the yeast Saccharomyces cerevisiae have helped define mechanisms underlying the activity of the ubiquitin–proteasome system (UPS), uncover the proteasome assembly pathway, and link the UPS to the maintenance of cellular homeostasis. However, the spectrum of UPS substrates is incompletely defined, even though multiple techniques—including MS—have been used. Therefore, we developed a substrate trapping proteomics workflow to identify previously unknown UPS substrates. We first generated a yeast strain with an epitope tagged proteasome subunit to which a proteasome inhibitor could be applied. Parallel experiments utilized inhibitor insensitive strains or strains lacking the tagged subunit. After affinity isolation, enriched proteins were resolved, in-gel digested, and analyzed by high resolution liquid chromatography-tandem MS. A total of 149 proteasome partners were identified, including all 33 proteasome subunits. When we next compared data between inhibitor sensitive and resistant cells, 27 proteasome partners were significantly enriched. Among these proteins were known UPS substrates and proteins that escort ubiquitinated substrates to the proteasome. We also detected Erg25 as a high-confidence partner. Erg25 is a methyl oxidase that converts dimethylzymosterol to zymosterol, a precursor of the plasma membrane sterol, ergosterol. Because Erg25 is a resident of the endoplasmic reticulum (ER) and had not previously been directly characterized as a UPS substrate, we asked whether Erg25 is a target of the ER associated degradation (ERAD) pathway, which most commonly mediates proteasome-dependent destruction of aberrant proteins. As anticipated, Erg25 was ubiquitinated and associated with stalled proteasomes. Further, Erg25 degradation depended on ERAD-associated ubiquitin ligases and was regulated by sterol synthesis. These data expand the cohort of lipid biosynthetic enzymes targeted for ERAD, highlight the role of the UPS in maintaining ER function, and provide a novel tool to uncover other UPS substrates via manipulations of our engineered strain.

scholarly journals A Functional Ubiquitin-Proteasome System is Required for Efficient Replication of New World Mayaro and Una Alphaviruses

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 370 ◽  
Author(s):  
Yessica Y. Llamas-González ◽  
Dalkiria Campos ◽  
Juan M. Pascale ◽  
Juan Arbiza ◽  
José González-Santamaría
Keyword(s):  
Plaque Assay ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Assay Method ◽  
Efficient Replication ◽  
Serological Studies ◽  
Ubiquitin Proteasome ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Mayaro (MAYV) and Una (UNAV) are emerging arboviruses belonging to the Alphavirus genus of the Togaviridae family. These viruses can produce febrile disease with symptoms such as fever, headache, myalgia, skin rash and incapacitating poly-arthralgia. Serological studies indicate that both viruses are circulating in different countries in Latin America. Viruses need the host cell machinery and resources to replicate effectively. One strategy to find new antivirals consists of identifying key cellular pathways or factors that are essential for virus replication. In this study, we analyzed the role of the ubiquitin-proteasome system (UPS) in MAYV and UNAV replication. Vero-E6 or HeLa cells were treated with the proteasome inhibitors MG132 or Lactacystin, and viral progeny production was quantified using a plaque assay method. In addition, the synthesis of viral proteins was analyzed by Western blot and confocal microscopy. Our results indicate that treatment with proteasome inhibitors decreases MAYV and UNAV protein synthesis, and also causes a significant dose-dependent decrease in MAYV and UNAV replication. Proteasome activity seems to be important at the early stages of MAYV replication. These findings suggest that the ubiquitin-proteasome system is a possible pharmacological target to inhibit these neglected alphaviruses.

Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3745-3755 ◽  
Author(s):  
Jacek Bil ◽  
Magdalena Winiarska ◽  
Dominika Nowis ◽  
Kamil Bojarczuk ◽  
Anna Dąbrowska-Iwanicka ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Negative Influence ◽  
Bafilomycin A1 ◽  
Short Term ◽  
Lymphoma Cells ◽  
Raji Cells ◽  
Complement Dependent Cytotoxicity ◽  
Ubiquitin Proteasome

Abstract Unresponsiveness to rituximab treatment develops in many patients prompting elucidation of underlying molecular pathways. It was recently observed that rituximab-resistant lymphoma cells exhibit up-regulation of components of the ubiquitin-proteasome system (UPS). Therefore, we investigated in more detail the role of this system in the regulation of CD20 levels and the influence of proteasome inhibitors on rituximab-mediated complement-dependent cytotoxicity (R-CDC). We observed that incubation of Raji cells with rituximab leads to increased levels of ubiquitinated CD20. However, inhibition of the UPS was not associated with up-regulation of surface CD20 levels, although it significantly increased its ubiquitination. Short-term (24 hours) incubation of Raji cells with 10 or 20nM bortezomib did not change surface CD20 levels, but sensitized CD20+ lymphoma cells to R-CDC. Prolonged (48 hours) incubation with 20nM bortezomib, or incubation with 50nM bortezomib for 24 hours led to a significant decrease in surface CD20 levels as well as R-CDC. These effects were partly reversed by bafilomycin A1, an inhibitor of lysosomal/autophagosomal pathway of protein degradation. These studies indicate that CD20 levels are regulated by 2 proteolytic systems and that the use of proteasome inhibitors may be associated with unexpected negative influence on R-CDC.

scholarly journals Fragment-Sized and Bidentate (Immuno)Proteasome Inhibitors Derived from Cysteine and Threonine Targeting Warheads

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3431
Author(s):  
Levente Kollár ◽  
Martina Gobec ◽  
Matic Proj ◽  
Lara Smrdel ◽  
Damijan Knez ◽  
...  
Keyword(s):  
Proteasome Inhibitors ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Protein Homeostasis ◽  
Single Digit ◽  
Ic50 Values ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome

Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for the protein homeostasis. Selective inhibition of the immunoproteasome offers opportunities for the treatment of numerous diseases, including inflammation, autoimmune diseases, and hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic inhibitors are sparse. Here, we describe two series of compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent immunoproteasome inhibitors are reported. Systematic substituent scans around the fragment core of benzoxazole-2-carbonitrile led to compounds with single digit micromolar inhibition of the β5i subunit. Experimental and computational reactivity studies revealed that the substituents do not affect the covalent reactivity of the carbonitrile warhead, but mainly influence the non-covalent recognition. Considering the small size of the inhibitors, this finding emphasizes the importance of the non-covalent recognition step in the covalent mechanism of action. As a follow-up series, bidentate inhibitors are disclosed, in which electrophilic heterocyclic fragments, i.e., 2-vinylthiazole, benzoxazole-2-carbonitrile, and benzimidazole-2-carbonitrile were linked to threonine-targeting (R)-boroleucine moieties. These compounds were designed to bind both the Thr1 and β5i-subunit-specific residue Cys48. However, inhibitory activities against (immuno)proteasome subunits showed that bidentate compounds inhibit the β5, β5i, β1, and β1i subunits with submicromolar to low-micromolar IC50 values. Inhibitory assays against unrelated enzymes showed that compounds from both series are selective for proteasomes. The presented nonpeptidic and covalent derivatives are suitable hit compounds for the development of either β5i-selective immunoproteasome inhibitors or compounds targeting multiple subunits of both proteasomes.

scholarly journals Current Understanding on the Role of Standard and Immunoproteasomes in Inflammatory/Immunological Pathways of Multiple Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Elena Bellavista ◽  
Aurelia Santoro ◽  
Daniela Galimberti ◽  
Cristoforo Comi ◽  
Fabio Luciani ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Current Knowledge ◽  
Ex Vivo ◽  
Critical Role ◽  
Proteasome Inhibitors ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Molecular Machinery

The ubiquitin-proteasome system is the major intracellular molecular machinery for protein degradation and maintenance of protein homeostasis in most human cells. As ubiquitin-proteasome system plays a critical role in the regulation of the immune system, it might also influence the development and progression of multiple sclerosis (MS). Bothex vivoanalyses and animal models suggest that activity and composition of ubiquitin-proteasome system are altered in MS. Proteasome isoforms endowed of immunosubunits may affect the functionality of different cell types such as CD8+and CD4+T cells and B cells as well as neurons during MS development. Furthermore, the study of proteasome-related biomarkers, such as proteasome antibodies and circulating proteasomes, may represent a field of interest in MS. Proteasome inhibitors are already used as treatment for cancer and the recent development of inhibitors selective for immunoproteasome subunits may soon represent novel therapeutic approaches to the different forms of MS. In this review we describe the current knowledge on the potential role of proteasomes in MS and discuss thepro et contraof possible therapies for MS targeting proteasome isoforms.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

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