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.

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 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.

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 The Ubiquitin-Proteasome System Is Necessary for Efficient Replication of Human Astrovirus

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Luis A. Casorla-Pérez ◽  
Tomás López ◽  
Susana López ◽  
Carlos F. Arias
Keyword(s):  
Protein Synthesis ◽  
Viral Protein ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Progeny Production ◽  
Viral Protein Synthesis ◽  
Viral Progeny ◽  
Efficient Replication ◽  
Ubiquitin Proteasome ◽  
Human Astrovirus

ABSTRACT Astroviruses, members of the family Astroviridae, represent an important cause of human gastroenteritis in the world. The cellular factors required for astrovirus replication have been poorly studied. In this work, we evaluated the relevance of the ubiquitin-proteasome system (UPS) in the replication of Yuc8, a human astrovirus serotype 8 strain. We found that proteasome inhibitors decrease the production of infectious viral progeny at a step in the replication cycle subsequent to virus entry. The inhibition of proteasome activity decreases viral RNA levels and viral protein synthesis; similarly, the inhibition of ubiquitination by chemical inhibitors or RNA interference (RNAi) reduces the production of viral progeny as well as viral protein synthesis. The effect on viral progeny production induced by proteasome inhibitors is not explained by a reduction in the pool of monoubiquitin or the induction of early apoptosis or autophagy. Our observations are consistent with the need of the proteolytic activity of the UPS for the efficient replication of the virus and suggest that UPS is necessary for the production of genomic and subgenomic RNA but not for antigenomic RNA. IMPORTANCE Astroviruses are a major cause of gastroenteritis in young humans and animals, and recently, it was associated with fatal encephalitis in humans. The role of the ubiquitin-proteasome system in the replication of these viruses has not been studied previously. In this work, we present evidence that supports that the proteolytic activity of the proteasome is necessary for efficient viral progeny production and that this proteolytic system is required for the accumulation of both genomic and subgenomic viral RNAs.

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.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

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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