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 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.

The role of SLAM family receptors in immune cell signalingThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 832-843 ◽  
Author(s):  
Elena A. Ostrakhovitch ◽  
Shawn S.-C. Li
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Types ◽  
Health And Disease ◽  
Slam Family ◽  
Different Cell Types ◽  
Selection Of

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.

Impact of Ubiquitination Signaling Pathway Modifications on Oral Carcinoma

2022 ◽  
Vol 2 (1) ◽  
pp. 1-6
Author(s):  
EFTHIMIOS KYRODIMOS ◽  
ARISTEIDIS CHRYSOVERGIS ◽  
NICHOLAS MASTRONIKOLIS ◽  
EVANGELOS TSIAMBAS ◽  
LOUKAS MANAIOS ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Broad Spectrum ◽  
Critical Role ◽  
Ubiquitin Proteasome System ◽  
Protein Targets ◽  
Metabolism Regulation ◽  
Substrate Protein ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation

Among intra-cellular homeostasis mechanisms, ubiquitination plays a critical role in protein metabolism regulation by degrading proteins via activating a broad spectrum of ubiquitin chains. In fact, ubiquitination and sumoylation signaling pathways are characterized by increased complexity regarding the molecules and their interactions. The Ubiquitin-Proteasome System (Ub-PS) recognizes and targets a broad spectrum of protein substrates. Ubiquitin conjugation modifies each substrate protein determining its biochemical fate (degradation). A major functional activity of Ub-PS is autophagy mechanism regulation. Interestingly, Ub-PS promotesall stages of bulk autophagy (initiation, execution, and termination). Autophagy is a crucial catabolic process that provides protein degradation and for this reason the interaction with Ub-PS is crucial. Furthermore, ubiquitination controls and regulates specific types of protein targets. Ub-PS is also involved in oxidative cellular stress and DNA damage response. Additionally, the functional role of Ub-PS in ribosome machinery regulation seems to be crucial. Concerning carcinogenesis, Ub-PS is involved in malignant disease development and progression by negatively affecting the corresponding TGF-B-, MEEK/MAPK/ERK-JNK- dependent signaling pathways. In the current review article, we describe the role of Ub-PSbiochemicalmodifications and alterations in oral squamous cell carcinoma (OSCC).

scholarly journals The Role of ATG16 in Autophagy and The Ubiquitin Proteasome System

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 2 ◽  
Author(s):  
Qiuhong Xiong ◽  
Wenjing Li ◽  
Ping Li ◽  
Min Yang ◽  
Changxin Wu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathways ◽  
Autophagosome Formation ◽  
Cell Homeostasis ◽  
Independent Functions ◽  
Ubiquitin Proteasome

Autophagy and the ubiquitin proteasome system (UPS) are the two major cellular degradation pathways, which are critical for the maintenance of cell homeostasis. The two pathways differ in their mechanisms and clients. The evolutionary conserved ATG16 plays a key role in autophagy and appears to link autophagy with the UPS. Here, we review the role of ATG16 in different species. We summarize the current knowledge of its functions in autophagosome membrane expansion and autophagosome formation, in Crohn’s disease, and in bacterial sequestration. In addition, we provide information on its autophagy-independent functions and its role in the crosstalk between autophagy and the UPS.

scholarly journals The E3 Ligases Spsb1 and Spsb4 Regulate RevErbα Degradation and Circadian Period

2019 ◽  
Vol 34 (6) ◽  
pp. 610-621 ◽  
Author(s):  
Tsedey Mekbib ◽  
Ting-Chung Suen ◽  
Aisha Rollins-Hairston ◽  
Jason P. DeBruyne
Keyword(s):  
Circadian Clock ◽  
Critical Role ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Clock Proteins ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Circadian Clock Proteins ◽  
The Stability

The time-dependent degradation of core circadian clock proteins is essential for the proper functioning of circadian timekeeping mechanisms that drive daily rhythms in gene expression and, ultimately, an organism’s physiology. The ubiquitin proteasome system plays a critical role in regulating the stability of most proteins, including the core clock components. Our laboratory developed a cell-based functional screen to identify ubiquitin ligases that degrade any protein of interest and have started screening for those ligases that degrade circadian clock proteins. This screen identified Spsb4 as a putative novel E3 ligase for RevErbα. In this article, we further investigate the role of Spsb4 and its paralogs in RevErbα stability and circadian rhythmicity. Our results indicate that the paralogs Spsb1 and Spsb4, but not Spsb2 and Spsb3, can interact with and facilitate RevErbα ubiquitination and degradation and regulate circadian clock periodicity.

scholarly journals Canonical and non-canonical autophagy pathways in microglia

2020 ◽  
Author(s):  
Julia Jülg ◽  
Laura Strohm ◽  
Christian Behrends
Keyword(s):  
Neurodegenerative Disorders ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Brain Health ◽  
The Past ◽  
Long Time ◽  
Ubiquitin Proteasome ◽  
Autophagy Activity

Besides the ubiquitin-proteasome-system, autophagy is a major degradation pathway within cells. It delivers invading pathogens, damaged organelles, aggregated proteins and other macromolecules from the cytosol to the lysosome for bulk degradation. This so-called canonical autophagy activity contributes to the maintenance of organelle, protein and metabolite homeostasis as well as innate immunity. Over the past years, numerous studies rapidly deepened our knowledge on the autophagy machinery and its regulation; driven by the fact that impairment of autophagy is associated with several human pathologies including cancer, immune diseases and neurodegenerative disorders. Unexpectedly, components of the autophagic machinery were also found to participate in various processes that did not involve lysosomal delivery of cytosolic constituents. These functions are hereafter defined as non-canonical autophagy. Regarding neurodegenerative diseases, most research was performed in neurons, while for a long-time microglia received considerably less attention. Concomitant with the notion that microglia greatly contribute to brain health, the understanding of the role of autophagy in microglia expanded. To facilitate an overview of the current knowledge, we present herein the fundamentals as well as the recent advances of canonical and non-canonical autophagy functions in microglia.

scholarly journals Doxorubicin and NRG-1/erbB4-Deficiency Affect Gene Expression Profile: Involving Protein Homeostasis in Mouse

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Cecilia Vasti ◽  
Henning Witt ◽  
Matilde Said ◽  
Patricia Sorroche ◽  
Hernán García-Rivello ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Ventricular Remodeling ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Neuregulin 1 ◽  
Hypertrophic Response ◽  
Ubiquitin Proteasome

The accumulating evidence demonstrates the essential role of neuregulin-1 signaling in the adult heart, and, moreover, indicates that an impaired neuregulin signaling exacerbates the doxorubicin-mediated cardiac toxicity. Despite this strong data, the specific cardiomyocyte targets of the active erbB2/erbB4 heterodimer remain unknown. In this paper, we examined pathways involved in cardiomyocyte damage as a result of the cardiac sensitization to anthracycline toxicity in the ventricular muscle-specific erbB4 knockout mouse. We performed morphological analyses to evaluate the ventricular remodeling and employed a cDNA microarray to assess the characteristic gene expression profile, verified data by real-time RT-PCR, and then grouped into functional categories and pathways. We confirm the upregulation of genes related to the classical signature of a hypertrophic response, implicating an erbB2-dependent mechanism in doxorubicin-treated erbB4-KO hearts. Our results indicate the remarkable downregulation of IGF-I/PI-3′ kinase pathway and extends our current knowledge by uncovering an altered ubiquitin-proteasome system leading to cardiomyocyte autophagic vacuolization.

scholarly journals The Role of Primary Cilia in the Crosstalk between the Ubiquitin–Proteasome System and Autophagy

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 241 ◽  
Author(s):  
Antonia Wiegering ◽  
Ulrich Rüther ◽  
Christoph Gerhardt
Keyword(s):  
Protein Degradation ◽  
Primary Cilia ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Review Article ◽  
The Other ◽  
Novel Studies ◽  
Safety Mechanism ◽  
Ubiquitin Proteasome

Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin–proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of safety mechanism. If one of these degradation systems is hampered, the other compensates for this defect. The mechanism behind this crosstalk is poorly understood. Novel studies suggest that primary cilia, little cellular protrusions, are involved in the regulation of the crosstalk between the two degradation systems. In this review article, we summarise the current knowledge about the association between cilia, the ubiquitin–proteasome system and autophagy.

scholarly journals Degradation and beyond: Control of androgen receptor activity by the proteasome system

2006 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomasz Jaworski
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Critical Role ◽  
Ubiquitin Proteasome System ◽  
Cancer Therapies ◽  
The Family ◽  
Prostate Cancer Development ◽  
Androgen Receptor Activity ◽  
Ubiquitin Proteasome

AbstractThe androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors which mediates the action of androgens in the development of urogenital structures. AR expression is regulated post-translationally by the ubiquitin/proteasome system. This regulation involves more complex mechanisms than typical degradation. The ubiquitin/proteasome system may regulate AR via mechanisms that do not engage in receptor turnover. Given the critical role of AR in sexual development, this complex regulation is especially important. Deregulation of AR signalling may be a causal factor in prostate cancer development. AR is the main target in prostate cancer therapies. Due to the critical role of the ubiquitin/proteasome system in AR regulation, current research suggests that targeting AR degradation is a promising approach.

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