Structure and Function of the Ubiquitin–Proteasome System

2012 ◽  
pp. 41-74 ◽  
Author(s):  
Niki Chondrogianni ◽  
Efstathios S. Gonos
Keyword(s):  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
Ubiquitin Proteasome ◽  
And Function

scholarly journals Structure and function of the ubiquitin‐proteasome system in platelets

2020 ◽  
Vol 18 (4) ◽  
pp. 771-780
Author(s):  
Lisa Colberg ◽  
Clemens Cammann ◽  
Andreas Greinacher ◽  
Ulrike Seifert
Keyword(s):  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
Ubiquitin Proteasome ◽  
And Function

scholarly journals Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

2020 ◽  
Vol 21 (17) ◽  
pp. 5962 ◽  
Author(s):  
Takashi Shiromizu ◽  
Mizuki Yuge ◽  
Kousuke Kasahara ◽  
Daishi Yamakawa ◽  
Takaaki Matsui ◽  
...  
Keyword(s):  
Essential Role ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
E3 Ubiquitin Ligases ◽  
Complex Disorders ◽  
Ciliary Function ◽  
Ubiquitin Proteasome ◽  
And Function

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.

scholarly journals Tearin' Up My Heart: Proteolysis in the Cardiac Sarcomere

2011 ◽  
Vol 286 (12) ◽  
pp. 9929-9934 ◽  
Author(s):  
Andrea L. Portbury ◽  
Monte S. Willis ◽  
Cam Patterson
Keyword(s):  
Cardiovascular Health ◽  
Ubiquitin Proteasome System ◽  
Structure And Function ◽  
Cardiac Sarcomere ◽  
Ubiquitin Proteasome ◽  
Health And Disease ◽  
The Individual ◽  
And Function ◽  
Calpain System

Proteolysis within the cardiac sarcomere is a constantly evolving area of research. Three major pathways of proteolysis have been identified as being active within the cardiac sarcomere, namely the ubiquitin-proteasome system, autophagy, and the calpain system. The role of ubiquitin-proteasome system-mediated proteolysis in cardiovascular health and disease has been known for some time; however, it is now apparent that other proteolytic systems also aid in the stabilization of cardiac sarcomere structure and function. This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere.

scholarly journals Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

2013 ◽  
Vol 31 (9) ◽  
pp. 1231-1238 ◽  
Author(s):  
Lindsey N. Micel ◽  
John J. Tentler ◽  
Peter G. Smith ◽  
Gail S. Eckhardt
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Regulation ◽  
Ubiquitin Chain ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Enzyme Families ◽  
And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

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.

To beat or not to beat: degradation of Cx43 imposes the heart rhythm

2015 ◽  
Vol 43 (3) ◽  
pp. 476-481 ◽  
Author(s):  
Tânia Martins-Marques ◽  
Steve Catarino ◽  
Carla Marques ◽  
Paulo Pereira ◽  
Henrique Girão
Keyword(s):  
Ischemia Reperfusion ◽  
Heart Rhythm ◽  
Ubiquitin Proteasome System ◽  
Cardiac Cells ◽  
Main Function ◽  
Metabolic Coupling ◽  
Heart Ischemia ◽  
Ubiquitin Proteasome ◽  
And Function ◽  
Fine Tune

The main function of the heart is to pump blood to the different parts of the organism, a task that is efficiently accomplished through proper electric and metabolic coupling between cardiac cells, ensured by gap junctions (GJ). Cardiomyocytes are the major cell population in the heart, and as cells with low mitotic activity, are highly dependent upon mechanisms of protein degradation. In the heart, both the ubiquitin-proteasome system (UPS) and autophagy participate in the fine-tune regulation of cardiac remodelling and function, either in physiological or pathological conditions. Indeed, besides controlling cardiac signalling pathways, UPS and autophagy have been implicated in the turnover of several myocardial proteins. Degradation of Cx43, the major ventricular GJ protein, has been associated to up-regulation of autophagy at the onset of heart ischemia and ischemia/reperfusion (I/R), which can have profound implications upon cardiac function. In this review, we present recent studies devoted to the involvement of autophagy and UPS in heart homoeostasis, with a particular focus on GJ.

scholarly journals The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans

2007 ◽  
Vol 177 (2) ◽  
pp. 205-210 ◽  
Author(s):  
Megan L. Landsverk ◽  
Shumin Li ◽  
Alex H. Hutagalung ◽  
Ayaz Najafov ◽  
Thorsten Hoppe ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Proteasome Inhibition ◽  
Thick Filament ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Myosin Motors ◽  
And Function ◽  
Sarcomere Assembly

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45–related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.

scholarly journals Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice

2008 ◽  
Vol 180 (6) ◽  
pp. 1177-1189 ◽  
Author(s):  
Jianjun Wang ◽  
Chuan-En Wang ◽  
Adam Orr ◽  
Suzanne Tydlacka ◽  
Shi-Hua Li ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Ubiquitin Proteasome System ◽  
Synaptic Function ◽  
Fluorescent Reporters ◽  
Biochemical Assays ◽  
Neuronal Processes ◽  
Ubiquitin Proteasome ◽  
And Function ◽  
Other Neurological Disease

Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin–proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models.

scholarly journals Comprehensive Study of Human FBXW7 Deleterious nsSNP's Functional Inference and Susceptibility to Gynaecological Cancer

2021 ◽  
Author(s):  
Archana Vasuki.K ◽  
Jemmy Christy.H
Keyword(s):  
Substrate Binding ◽  
Interaction Network ◽  
Ubiquitin Proteasome System ◽  
Protein Protein Interaction ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Causes Of Mortality ◽  
Functional Inference ◽  
Wd40 Domain ◽  
And Function

Abstract Cancer is one of the world's major causes of mortality, and it plays a most important role in the world's declining life expectancy. F-box and WD-40 domain protein 7 (FBXW7), a typical participant of the F-box family of proteins, has been considered as an antitumor protein and one of the maximum deregulated ubiquitin-proteasome system proteins in uterine carcinosarcoma, endometrial clear cell carcinoma and cervical carcinoma with the greatest prevalence of alterations. FBXW7 variants with known clinical significance, as well as nsSNP’s in the F-Box and WD40 domains, were evaluated using functionality prediction web resources. Upon analysing the seventy-three deleterious nsSNP’s impact on protein stability and function, we identified that forty-one nsSNP’s of WD40 domain and three of F-Box domain imply decreased stability of the FBXW7 structure. Next to TP53 and PTEN, FBXW7 was reported with the highest percentage of arginine substitution among mutations related to cancer. The current research concentrated on two arginine residue locations (Arg465, Arg505) within the WD40-repeat domain, which is vital for substrate binding. Computational analysis revealed that significant deviation in stability and structural configuration of mutants R505L, R465H, R465P, R505G, R505C, R465C R505S and R505L structures. Protein–protein interaction network of FBXW7 populated with promising hub proteins NOTCH1, c-Myc, CCNE1, STYX, KLG5, SREB1, NFKB2, SKP1, CUL1, thus alteration in the FBXW7 leads to aberration in their signalling pathways as well as their substrate binding ability makes this protein as attractive target for personalized therapeutic intervention.

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