scholarly journals Selective Accumulation of Aggregation-Prone Proteasome Substrates in Response to Proteotoxic Stress

2009 ◽  
Vol 29 (7) ◽  
pp. 1774-1785 ◽  
Author(s):  
Florian A. Salomons ◽  
Victoria Menéndez-Benito ◽  
Claudia Böttcher ◽  
Brett A. McCray ◽  
J. Paul Taylor ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Insoluble Protein ◽  
Conformational Diseases ◽  
Proteotoxic Stress ◽  
Ubiquitin Proteasome ◽  
Consistent Feature ◽  
Stressed Cells ◽  
Underlying Mechanisms ◽  
Selective Accumulation ◽  
Free Ubiquitin

ABSTRACT Conditions causing an increase in misfolded or aberrant proteins can impair the activity of the ubiquitin/proteasome system (UPS). This observation is of particular interest, given the fact that proteotoxic stress is closely associated with a large variety of disorders. Although impairment of the UPS appears to be a general consequence of proteotoxic insults, the underlying mechanisms remain enigmatic. Here, we show that heat shock-induced proteotoxic stress resulted in conjugation of ubiquitin to detergent-insoluble protein aggregates, which coincided with reduced levels of free ubiquitin and impediment of ubiquitin-dependent proteasomal degradation. Interestingly, whereas soluble proteasome substrates returned to normal levels after a transient accumulation, the levels of an aggregation-prone substrate remained high even when the free ubiquitin levels were restored. Consistently, overexpression of ubiquitin prevented accumulation of soluble but not aggregation-prone substrates in thermally stressed cells. Notably, cells were also unable to resume degradation of aggregation-prone substrates after treatment with the translation inhibitor puromycin, indicating that selective accumulation of aggregation-prone proteins is a consistent feature of proteotoxic stress. Our data suggest that the failure of the UPS to clear aggregated proteins in the aftermath of proteotoxic stress episodes may contribute to the selective deposition of aggregation-prone proteins in conformational diseases.

scholarly journals Selective autophagic clearance of protein aggregates is mediated by the autophagy receptor, TAX1BP1

2019 ◽  
Author(s):  
Shireen A. Sarraf ◽  
Hetal V. Shah ◽  
Gil Kanfer ◽  
Michael E. Ward ◽  
Richard J. Youle
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Cellular Homeostasis ◽  
Receptor Proteins ◽  
Proteotoxic Stress ◽  
Polyq Protein ◽  
Ubiquitin Proteasome

AbstractMisfolded protein aggregates can disrupt cellular homeostasis and cause toxicity, a hallmark of numerous neurodegenerative diseases. Protein quality control by the ubiquitin proteasome system (UPS) and autophagy is vital for clearance of aggregates and maintenance of cellular homeostasis1. Autophagy receptor proteins bridge the interaction between ubiquitinated proteins and the autophagy machinery allowing selective elimination of cargo2. Aggrephagy is critical to protein quality control, but how aggregates are recognized and targeted for degradation is not well understood. Here we examine the requirements for 5 autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in proteotoxic stress-induced aggregate clearance. Endogenous TAX1BP1 is both recruited to and required for the clearance of stress-induced aggregates while overexpression of TAX1BP1 increases aggregate clearance through autophagy. Furthermore, TAX1BP1 depletion sensitizes cells to proteotoxic stress and Huntington’s disease-linked polyQ proteins, whereas TAX1BP1 overexpression clears cells of polyQ protein aggregates by autophagy. We propose a broad role for TAX1BP1 in the clearance of cytotoxic proteins, thus identifying a new mode of clearance of protein inclusions.

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.

scholarly journals The Degradation-promoting Roles of Deubiquitinases Ubp6 and Ubp3 in Cytosolic and ER Protein Quality Control

2020 ◽  
Author(s):  
Hongyi Wu ◽  
Davis T.W. Ng ◽  
Ian Cheong ◽  
Paul Matsudaira
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Free Ubiquitin

AbstractThe quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome system. However, it remains unclear whether and how protein quality control deploys various deubiquitinases. To address this question, we screened deletions or mutation of the 20 deubiquitinase genes in Saccharomyces cerevisiae and discovered that almost half of the mutations slowed the removal of misfolded proteins whereas none of the remaining mutations accelerated this process significantly. Further characterization revealed that Ubp6 maintains the level of free ubiquitin to promote the elimination of misfolded cytosolic proteins, while Ubp3 supports the degradation of misfolded cytosolic and ER luminal proteins by different mechanisms.

Muscle Atrophy Classification: The Need for a Pathway-Driven Approach

2021 ◽  
Vol 27 ◽  
Author(s):  
John Zizzo
Keyword(s):  
Physical Activity ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Specific Region ◽  
Signaling Cascades ◽  
Impaired Ability ◽  
Neurogenic Atrophy ◽  
Ubiquitin Proteasome ◽  
Underlying Mechanisms

: It is well known that muscles can waste away (atrophy) due to a lack of physical activity. Muscle wasting commonly presents with reduced muscle strength and an impaired ability to perform daily tasks. Several studies have attempted to categorize muscle atrophy into three main subgroups: physiologic, pathologic, and neurogenic atrophy. Physiologic atrophy is caused by the general underuse of skeletal muscle (e.g., bedridden). Pathologic atrophy is characterized as the loss of stimulus to a specific region (e.g. aging). Neurogenic atrophy results from damage to the nerve innervating a muscle (e.g. SMA, GBS). Mechanisms have been elucidated for many of these pathways (e.g., ubiquitin-proteasome system, NF-κB, etc.). However, many causes of muscle atrophy (e.g., burns, arthritis, etc.) operate through unelucidated signaling cascades. Therefore, this review highlights the underlying mechanisms of each subtype of muscle atrophy while emphasizing the need for additional research in properly classifying and identifying muscle atrophy.

scholarly journals NEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Chantal M. Maghames ◽  
Sofia Lobato-Gil ◽  
Aurelien Perrin ◽  
Helene Trauchessec ◽  
Manuel S. Rodriguez ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Nuclear Protein ◽  
Ubiquitin Proteasome System ◽  
Proteotoxic Stress ◽  
Ubiquitin Proteasome

scholarly journals Hyperactivation of the proteasome core particle in Caenorhabditis elegans protects against proteotoxic stress and extends lifespan

2021 ◽  
Author(s):  
Raymond Anderson ◽  
Thomas Bradley ◽  
David Smith
Keyword(s):  
Caenorhabditis Elegans ◽  
Ubiquitin Proteasome System ◽  
Core Particle ◽  
C Elegans ◽  
Proteotoxic Stress ◽  
Age Related ◽  
Gating Mechanism ◽  
Ubiquitin Proteasome ◽  
Degradation Activity ◽  
Unstructured Protein

Abstract Many age-related diseases (ARDs) including virtually all neurodegenerative diseases (NDs) are characterized by the accumulation of proteins that are thought to significantly contribute to disease pathogenesis. One of the cell’s primary systems for the degradation of misfolded/damaged proteins is the Ubiquitin Proteasome System (UPS), and its impairment is implicated in essentially all NDs. Thus, upregulating this system to combat NDs has garnered a great deal of interest in recent years. Various animal models have focused on increasing the total proteasome levels, but thus far, none have focused on intrinsic activation of the proteasome itself. With this in mind, we constructed a, first to our knowledge, animal model that endogenously expresses a hyperactive open-gate proteasome in Caenorhabditis elegans (C. elegans). The gate-destabilizing mutation introduced into the nematode germline created a viable nematode population with substantially enhanced proteasomal peptidase and unstructured protein degradation activity. These CRISPR edited nematodes showed a significantly increased lifespan and substantial resistance to oxidative/proteotoxic stress with surprisingly mild consequential phenotypes. These results show that introducing a constitutively active proteasome into a multicellular organism is feasible and suggests targeting the proteasome gating mechanism as a valid approach for future ARD research efforts in mammals.

scholarly journals Autophagy: Vanquisher of the "Unseen Dangers" in Neurodegenerative Diseases?

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Alex Chun Koon
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Insoluble Protein ◽  
Toxic Species ◽  
Ubiquitin Proteasome ◽  
Soluble Species ◽  
Polyq Diseases ◽  
Lateral Sclerosis

Aggregation of misfolded proteins is a hallmark of many neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and polyglutamine (polyQ) diseases. Clearance of misfolded proteins in the cell relies on the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system. Since their discoveries, the UPS and autophagy were once thought to be independent of each other in terms of components, mechanisms and substrate selectivity. The UPS was believed to be responsible for degrading soluble proteins, whereas autophagy for degrading insoluble protein aggregates. However, recent studies have demonstrated that the insoluble protein aggregates may not be cytotoxic. By contrast, after deaggregation, multimers and microaggregates may still be present in the cell causing cytotoxicity. The UPS is incapable of degrading these soluble and semi-soluble species, and the vital task of degradation these toxic species rests upon the autophagy-lysosome system. Therefore, apart from degrading the visible protein aggregates, autophagy is also responsible for eliminating these “invisible dangers” to protect the cell in neurodegenerative diseases.

scholarly journals The Deubiquitylating Enzyme Ubp12 Regulates Rad23-Dependent Substrate Delivery at the Proteasome

2017 ◽  
Author(s):  
Daniela Gödderz ◽  
Nico P. Dantuma
Keyword(s):  
Dna Repair ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Misfolded Proteins ◽  
Proteotoxic Stress ◽  
Lysine Residues ◽  
Regulatory Link ◽  
Ubiquitin Proteasome ◽  
Summary Statement

AbstractThe consecutive actions of the ubiquitin-selective segregase Cdc48 and the ubiquitin shuttle factor Rad23 result in the delivery of ubiquitylated proteins at the proteasome. Here, we show that the deubiquitylating enzyme Ubp12 interacts with Cdc48 and regulates proteasomal degradation of Rad23-dependent substrates. Overexpression of Ubp12 results in stabilization of Rad23-dependent substrates. We show that Ubp12 removes short ubiquitin chains from the N-terminal ubiquitin-like domain (UbL) of Rad23. Preventing ubiquitylation of Rad23 by substitution of lysine residues within the UbL domain, Rad23UbLK0, does not affect the non-proteolytic role of Rad23 in DNA repair but causes an increase in ubiquitylated cargo bound to the UBA2 domains of Rad23 and recapitulates the stabilization of Rad23-dependent substrates observed upon overexpression of Ubp12. Expression of Rad23UbLK0or overexpression of Ubp12 impairs the ability of yeast to cope with proteotoxic stress consistent with inefficient clearance of misfolded proteins by the ubiquitin/proteasome system. Our data suggest that ubiquitylation of Rad23 plays a stimulatory role in facilitating the transfer of ubiquitylated substrates to the proteasome.Summary statementUbiquitylation of a ubiquitin shuttle factor regulates the delivery of substrates at the proteasome, uncovering a novel regulatory link between ubiquitin and proteasomal degradation.

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