scholarly journals The Roles of Ubiquitin in Mediating Autophagy

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2025 ◽  
Author(s):  
Zhangyuan Yin ◽  
Hana Popelka ◽  
Yuchen Lei ◽  
Ying Yang ◽  
Daniel J. Klionsky
Keyword(s):  
Molecular Mechanisms ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Post Translational Modification ◽  
Subcellular Organelles ◽  
Precise Control ◽  
Ubiquitin Proteasome ◽  
Autophagy Pathway ◽  
Structural Architecture ◽  
Related Proteins

Ubiquitination, the post-translational modification essential for various intracellular processes, is implicated in multiple aspects of autophagy, the major lysosome/vacuole-dependent degradation pathway. The autophagy machinery adopted the structural architecture of ubiquitin and employs two ubiquitin-like protein conjugation systems for autophagosome biogenesis. Ubiquitin chains that are attached as labels to protein aggregates or subcellular organelles confer selectivity, allowing autophagy receptors to simultaneously bind ubiquitinated cargos and autophagy-specific ubiquitin-like modifiers (Atg8-family proteins). Moreover, there is tremendous crosstalk between autophagy and the ubiquitin-proteasome system. Ubiquitination of autophagy-related proteins or regulatory components plays significant roles in the precise control of the autophagy pathway. In this review, we summarize and discuss the molecular mechanisms and functions of ubiquitin and ubiquitination, in the process and regulation of autophagy.

scholarly journals Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2121
Author(s):  
Emma I. Kane ◽  
Kelly L. Waters ◽  
Donald E. Spratt
Keyword(s):  
Molecular Mechanisms ◽  
Ubiquitin Proteasome System ◽  
Post Translational Modification ◽  
Ubiquitin Chain ◽  
Post Translational Modifications ◽  
Specific Attachment ◽  
Ubiquitin Proteasome ◽  
Cellular Pathways ◽  
Intracellular Fate ◽  
Chain Type

Neurodegeneration has been predominantly recognized as neuronal breakdown induced by the accumulation of aggregated and/or misfolded proteins and remains a preliminary factor in age-dependent disease. Recently, critical regulating molecular mechanisms and cellular pathways have been shown to induce neurodegeneration long before aggregate accumulation could occur. Although this opens the possibility of identifying biomarkers for early onset diagnosis, many of these pathways vary in their modes of dysfunction while presenting similar clinical phenotypes. With selectivity remaining difficult, it is promising that these neuroprotective pathways are regulated through the ubiquitin-proteasome system (UPS). This essential post-translational modification (PTM) involves the specific attachment of ubiquitin onto a substrate, specifically marking the ubiquitin-tagged protein for its intracellular fate based upon the site of attachment, the ubiquitin chain type built, and isopeptide linkages between different ubiquitin moieties. This review highlights both the direct and indirect impact ubiquitylation has in oxidative stress response and neuroprotection, and how irregularities in these intricate processes lead towards the onset of neurodegenerative disease (NDD).

scholarly journals USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro

2019 ◽  
Vol 20 (21) ◽  
pp. 5300 ◽  
Author(s):  
Kyung Ho Han ◽  
Minseok Kwak ◽  
Tae Hyeong Lee ◽  
Min-soo Park ◽  
In-ho Jeong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Ubiquitin Proteasome System ◽  
Migration And Invasion ◽  
Deubiquitinating Enzyme ◽  
Lung Tumorigenesis ◽  
Ubiquitin Chain ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Autophagy Pathway

The ubiquitin–proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment.

scholarly journals Progress in the pathogenesis and genetics of Parkinson's disease

2008 ◽  
Vol 363 (1500) ◽  
pp. 2215-2227 ◽  
Author(s):  
Yoshikuni Mizuno ◽  
Nobutaka Hattori ◽  
Shin-ichiro Kubo ◽  
Shigeto Sato ◽  
Kenya Nishioka ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Ubiquitin Proteasome System ◽  
Neurodegenerative Process ◽  
Molecular Events ◽  
Ubiquitin Proteasome ◽  
Sporadic Parkinson’S Disease ◽  
Synuclein Proteins

Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1 -linked PD due to α - synuclein ( SNCA ) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of α-synuclein. In PARK1 -linked PD, mutant α-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin–proteasome system and autophagy–lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

2016 ◽  
Vol 311 (3) ◽  
pp. C392-C403 ◽  
Author(s):  
Philippe A. Bilodeau ◽  
Erin S. Coyne ◽  
Simon S. Wing
Keyword(s):  
Signaling Pathways ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Clinical Problem ◽  
Ubiquitin Proteasome System ◽  
Mechanisms Of Action ◽  
Loss Of Function ◽  
Critical Determinant ◽  
Ubiquitin Proteasome

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.

scholarly journals The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover

2011 ◽  
Vol 22 (3) ◽  
pp. 291-300 ◽  
Author(s):  
Shan Xu ◽  
Guihong Peng ◽  
Yang Wang ◽  
Shengyun Fang ◽  
Mariusz Karbowski
Keyword(s):  
Mitochondrial Membrane ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Outer Mitochondrial Membrane ◽  
Aaa Atpase ◽  
Associated Proteins ◽  
Ubiquitin Proteasome ◽  
Molecular Components

Recent studies have revealed a role for the ubiquitin/proteasome system in the regulation and turnover of outer mitochondrial membrane (OMM)-associated proteins. Although several molecular components required for this process have been identified, the mechanism of proteasome-dependent degradation of OMM-associated proteins is currently unclear. We show that an AAA-ATPase, p97, is required for the proteasomal degradation of Mcl1 and Mfn1, two unrelated OMM proteins with short half-lives. A number of biochemical assays, as well as imaging of changes in localization of photoactivable GFP-fused Mcl1, revealed that p97 regulates the retrotranslocation of Mcl1 from mitochondria to the cytosol, prior to, or concurrent with, proteasomal degradation. Mcl1 retrotranslocation from the OMM depends on the activity of the ATPase domain of p97. Furthermore, p97-mediated retrotranslocation of Mcl1 can be recapitulated in vitro, confirming a direct mitochondrial role for p97. Our results establish p97 as a novel and essential component of the OMM-associated protein degradation pathway.

scholarly journals Abnormal Ubiquitination of Ubiquitin-Proteasome System in Lung Squamous Cell Carcinomas

2020 ◽  
Author(s):  
Xianquan Zhan ◽  
Miaolong Lu
Keyword(s):  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Lung Squamous Cell Carcinoma ◽  
Ubiquitin Proteasome System ◽  
Quantitative Information ◽  
Scientific Data ◽  
Label Free ◽  
Ubiquitinated Proteins ◽  
The Status ◽  
Ubiquitin Proteasome

Ubiquitination is an important post-translational modification. Abnormal ubiquitination is extensively associated with cancers. Lung squamous cell carcinoma (LUSC) is the most common pathological type of lung cancer, with unclear molecular mechanism and the poor overall prognosis of LUSC patient. To uncover the existence and potential roles of ubiquitination in LUSC, label-free quantitative ubiquitomics was performed in human LUSC vs. control tissues. In total, 627 ubiquitinated proteins (UPs) with 1209 ubiquitination sites were identified, including 1133 (93.7%) sites with quantitative information and 76 (6.3%) sites with qualitative information. KEGG pathway enrichment analysis found that UPs were significantly enriched in ubiquitin-mediated proteolysis pathway (hsa04120) and proteasome complex (hsa03050). Further analysis of 400 differentially ubiquitinated proteins (DUPs) revealed that 11 subunits of the proteasome complex were differentially ubiquitinated. These findings clearly demonstrated that ubiquitination was widely present in the ubiquitin-proteasome pathway in LUSCs. At the same time, abnormal ubiquitination might affect the function of the proteasome to promote tumorigenesis and development. This book chapter discussed the status of protein ubiquitination in the ubiquitin-proteasome system (UPS) in human LUSC tissues, which offered the scientific data to elucidate the specific molecular mechanisms of abnormal ubiquitination during canceration and the development of anti-tumor drugs targeting UPS.

scholarly journals Effects of Exercise, Metformin, Pioglitazone and Exenatide Treatment on Inflammation Induced Insulin Resistance and Ubiquitin Proteasome System in Diabetes and Obesity

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A438-A438
Author(s):  
Ersin Akarsu ◽  
Can Demirel ◽  
Sibel Oguzkan Balci ◽  
Zeynel A Sayiner ◽  
İbrahim Yilmaz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Liver Tissue ◽  
Molecular Mechanisms ◽  
Immunohistochemical Analysis ◽  
Ubiquitin Proteasome System ◽  
Diabetic Animal ◽  
Ubiquitin Proteasome ◽  
Treatment Of Diabetes ◽  
Diabetes And Obesity

Abstract Purpose: The aim of this study is; To examine the destruction of insulin receptor substrate-1 (IRS-1) molecule, which is one of the mechanisms that cause insulin resistance in diabetes and obesity, and its effect to reduce this destruction. For this purpose, the effects of exercise, metformin, exenatide and pioglitazone treatments on IRS-1 ubiquitination in pancreas, muscle and adipose tissue were investigated in an obese and diabetic animal model. Method: Obese rat model was used in this study. This model is characterised by obesity, diabetes and insulin resistance. This study investigated the molecular mechanisms of IRS-1 breakdown in diabetes. IRS1, SOCS1, SOC3 expressions were evaluated in the liver, muscle and adipose tissue of this model. At the same time, immunohistochemical analyses were performed in terms of IRS1, SOCS1 and SOCS3 in the same tissues. Results: Gene expression and Immunohistochemical analysis results were evaluated, the increase in IRS1 was noticeable in rats treated with exenatide, especially in the liver tissue despite the greater decrease in SOCS1 (P> 0.05). It was determined that other drugs in this study and used in the treatment of diabetes may also affect this mechanism to different degrees. Conclusion: Our findings showed that some drugs used in the treatment of diabetes may alter the SOCS effect and / or proteasomal degradation of the IRS-1 protein. This effect was particularly pronounced in liver tissue. However, more comprehensive studies are required to show the contribution of ubiquitination in the destruction of IRS-1 and which drugs are effective on this mechanism. Acknowledgement: This study was supported by the Scientific And Tecnological Research Council Of Turkey (TÜBİTAK) Project No: 217S089

scholarly journals Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

Biomolecules ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 217 ◽  
Author(s):  
Milic ◽  
Tian ◽  
Bernhagen
Keyword(s):  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Cop9 Signalosome ◽  
Ring E3 Ligase ◽  
Ubiquitin Proteasome ◽  
Underlying Mechanisms ◽  
Isopeptidase Activity

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8. The main biochemical function of the CSN is the control of protein degradation via the ubiquitin-proteasome-system through regulation of cullin-RING E3-ligase (CRL) activity by deNEDDylation of cullins, but the CSN also serves as a docking platform for signaling proteins. The catalytic deNEDDylase (isopeptidase) activity of the complex is executed by CSN5, but only efficiently occurs in the three-dimensional architectural context of the complex. Due to its positioning in a central cellular pathway connected to cell responses such as cell-cycle, proliferation, and signaling, the CSN has been implicated in several human diseases, with most evidence available for a role in cancer. However, emerging evidence also suggests that the CSN is involved in inflammation and cardiovascular diseases. This is both due to its role in controlling CRLs, regulating components of key inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and complex-independent interactions of subunits such as CSN5 with inflammatory proteins. In this case, we summarize and discuss studies suggesting that the CSN may have a key role in cardiovascular diseases such as atherosclerosis and heart failure. We discuss the implicated molecular mechanisms ranging from inflammatory NF-κB signaling to proteotoxicity and necrosis, covering disease-relevant cell types such as myeloid and endothelial cells or cardiomyocytes. While the CSN is considered to be disease-exacerbating in most cancer entities, the cardiovascular studies suggest potent protective activities in the vasculature and heart. The underlying mechanisms and potential therapeutic avenues will be critically discussed.

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