Protein Quality Control Degradation in the Nucleus

Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins’ toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

Download Full-text

Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance

Biomolecules ◽

10.3390/biom11010054 ◽

2021 ◽

Vol 11 (1) ◽

pp. 54

Author(s):

Dina Franić ◽

Klara Zubčić ◽

Mirta Boban

Keyword(s):

Quality Control ◽

Protein Misfolding ◽

Protein Quality ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Cytoplasmic Proteins ◽

Ubiquitin Proteasome ◽

A Cell ◽

Protein Misfolding And Aggregation ◽

Order Complexes

Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.

Download Full-text

Neurodegenerative Diseases as Protein Misfolding Disorders

10.1093/med/9780190233563.003.0002 ◽

2016 ◽

Author(s):

Tomohiro Nakamura ◽

Stuart A. Lipton

Keyword(s):

Quality Control ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Protein Quality ◽

Protein S ◽

Ubiquitin Proteasome System ◽

Misfolded Proteins ◽

Redox Stress ◽

Chemical Mechanisms ◽

Ubiquitin Proteasome

Neurodegenerative diseases (NDDs) often represent disorders of protein folding. Rather than large aggregates, recent evidence suggests that soluble oligomers of misfolded proteins are the most neurotoxic species. Emerging evidence points to small, soluble oligomers of misfolded proteins as the cause of synaptic dysfunction and loss, the major pathological correlate to disease progression in many NDDs including Alzheimer’s disease. The protein quality control machinery of the cell, which includes molecular chaperones as found in the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS), and various forms of autophagy, can counterbalance the accumulation of misfolded proteins to some extent. Their ability to eliminate the neurotoxic effects of misfolded proteins, however, declines with age. A plausible explanation for the age-dependent deterioration of the quality control machinery involves compromise of these systems by excessive generation of reactive oxygen species (ROS), such as superoxide anion (O2-), and reactive nitrogen species (RNS), such as nitric oxide (NO). The resulting redox stress contributes to the accumulation of misfolded proteins. Here, we focus on aberrantly increased generation of NO-related species since this process appears to accelerate the manifestation of key neuropathological features, including protein misfolding. We review the chemical mechanisms of posttranslational modification by RNS such as protein S-nitrosylation of critical cysteine thiol groups and nitration of tyrosine residues, showing how they contribute to the pathogenesis of NDDs.

Download Full-text

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

10.1101/2020.01.22.915793 ◽

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.

Download Full-text

Protein Quality Control of the Endoplasmic Reticulum and Ubiquitin–Proteasome-Triggered Degradation of Aberrant Proteins: Yeast Pioneers the Path

Annual Review of Biochemistry ◽

10.1146/annurev-biochem-062917-012749 ◽

2018 ◽

Vol 87 (1) ◽

pp. 751-782 ◽

Cited By ~ 51

Author(s):

Nicole Berner ◽

Karl-Richard Reutter ◽

Dieter H. Wolf

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Protein Quality ◽

Protein Structures ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Misfolded Proteins ◽

Secretory Proteins ◽

Structural Alterations ◽

Ubiquitin Proteasome

Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified. A highly elaborated machinery controls their folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol. In the cytosol, they are degraded by the highly selective ubiquitin–proteasome system. This process of protein quality control followed by proteasomal elimination of the misfolded protein is termed ER-associated degradation (ERAD), and it depends on an intricate interplay between the ER and the cytosol.

Download Full-text

Mitochondrial Protein Quality Control Mechanisms

Genes ◽

10.3390/genes11050563 ◽

2020 ◽

Vol 11 (5) ◽

pp. 563 ◽

Cited By ~ 4

Author(s):

Pooja Jadiya ◽

Dhanendra Tomar

Keyword(s):

Quality Control ◽

Protein Import ◽

Protein Quality ◽

Current Knowledge ◽

Mitochondrial Protein ◽

Protein Quality Control ◽

Redox Balance ◽

Ubiquitin Proteasome System ◽

Control Mechanisms ◽

Mitochondrial Proteome

Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.

Download Full-text

Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast Protein Quality Control

Biomolecules ◽

10.3390/biom11121821 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1821

Author(s):

Carolyn Allain Breckel ◽

Mark Hochstrasser

Keyword(s):

Quality Control ◽

Ubiquitin Ligase ◽

Protein Quality ◽

Three Dimensional ◽

Protein Quality Control ◽

Ubiquitin Ligases ◽

Ubiquitin Proteasome System ◽

Current Evidence ◽

Cellular Processes ◽

Cellular Compartments

The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments.

Download Full-text

How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases

International Journal of Molecular Sciences ◽

10.3390/ijms22042078 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2078

Author(s):

Ji An Kang ◽

Young Joo Jeon

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Molecular Mechanisms ◽

Protein Quality ◽

Protein Quality Control ◽

Ubiquitin Ligases ◽

Ubiquitin Proteasome System ◽

Misfolded Proteins ◽

E3 Ubiquitin Ligases ◽

Quantity Control

The endoplasmic reticulum (ER) is an interconnected organelle that plays fundamental roles in the biosynthesis, folding, stabilization, maturation, and trafficking of secretory and transmembrane proteins. It is the largest organelle and critically modulates nearly all aspects of life. Therefore, in the endoplasmic reticulum, an enormous investment of resources, including chaperones and protein folding facilitators, is dedicated to adequate protein maturation and delivery to final destinations. Unfortunately, the folding and assembly of proteins can be quite error-prone, which leads to the generation of misfolded proteins. Notably, protein homeostasis, referred to as proteostasis, is constantly exposed to danger by flows of misfolded proteins and subsequent protein aggregates. To maintain proteostasis, the ER triages and eliminates terminally misfolded proteins by delivering substrates to the ubiquitin–proteasome system (UPS) or to the lysosome, which is termed ER-associated degradation (ERAD) or ER-phagy, respectively. ERAD not only eliminates misfolded or unassembled proteins via protein quality control but also fine-tunes correctly folded proteins via protein quantity control. Intriguingly, the diversity and distinctive nature of E3 ubiquitin ligases determine efficiency, complexity, and specificity of ubiquitination during ERAD. ER-phagy utilizes the core autophagy machinery and eliminates ERAD-resistant misfolded proteins. Here, we conceptually outline not only ubiquitination machinery but also catalytic mechanisms of E3 ubiquitin ligases. Further, we discuss the mechanistic insights into E3 ubiquitin ligases involved in the two guardian pathways in the ER, ERAD and ER-phagy. Finally, we provide the molecular mechanisms by which ERAD and ER-phagy conduct not only protein quality control but also protein quantity control to ensure proteostasis and subsequent organismal homeostasis.

Download Full-text

HSP70-binding motifs function as protein quality control degrons

10.1101/2021.12.22.473789 ◽

2021 ◽

Author(s):

Amanda B Abildgaard ◽

Søren D Petersen ◽

Fia B Larsen ◽

Caroline Kampmeyer ◽

Kristoffer E Johansson ◽

...

Keyword(s):

Quality Control ◽

Protein Quality ◽

Protein Quality Control ◽

Ubiquitin Proteasome System ◽

Misfolded Proteins ◽

Binding Motif ◽

Binding Motifs ◽

C Terminus ◽

Ubiquitin Proteasome ◽

Chaperone Binding

Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for degradation through the ubiquitin-proteasome system (UPS). To uncover how PQC degrons function, we performed a screen in Saccharomyces cerevisiae by fusing a library of flexible tetrapeptides to the C-terminus of the Ura3-HA-GFP reporter. The identified degrons exhibited high sequence variation but with marked hydrophobicity. Notably, the best scoring degrons constitute predicted Hsp70-binding motifs. When directly tested, a canonical Hsp70 binding motif (RLLL) functioned as a dose-dependent PQC degron that was targeted by Hsp70, Hsp110, Fes1, several Hsp40 J-domain co-chaperones and the PQC E3 ligase Ubr1. Our results suggest that multiple PQC degrons overlap with chaperone-binding sites and that PQC-linked degradation achieves specificity via chaperone binding. Thus, the PQC system has evolved to exploit the intrinsic capacity of chaperones to recognize misfolded proteins, thereby placing them at the nexus of protein folding and degradation.

Download Full-text

USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2014349117 ◽

2020 ◽

Vol 117 (45) ◽

pp. 28114-28125

Author(s):

Tao Zhang ◽

Goran Periz ◽

Yu-Ning Lu ◽

Jiou Wang

Keyword(s):

Quality Control ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Mammalian Cells ◽

Transforming Growth Factor ◽

Protein Quality ◽

Protein Quality Control ◽

Transforming Growth Factor Β ◽

Misfolded Proteins ◽

A Genome

An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in aCaenorhabditis elegansmodel of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved inDrosophilaand mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.

Download Full-text

Parkin-mediated ubiquitin signalling in aggresome formation and autophagy

Biochemical Society Transactions ◽

10.1042/bst0380144 ◽

2010 ◽

Vol 38 (1) ◽

pp. 144-149 ◽

Cited By ~ 89

Author(s):

Lih-Shen Chin ◽

James A. Olzmann ◽

Lian Li

Keyword(s):

Protein Misfolding ◽

Current Knowledge ◽

Ubiquitin Proteasome System ◽

Misfolded Proteins ◽

Proteotoxic Stress ◽

Ubiquitin Proteasome ◽

Autophagy Pathway ◽

Aggresome Formation ◽

Protein Misfolding And Aggregation ◽

Cellular Defence

Understanding how cells handle and dispose of misfolded proteins is of paramount importance because protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative disorders, including PD (Parkinson's disease) and Alzheimer's disease. In addition to the ubiquitin–proteasome system, the aggresome–autophagy pathway has emerged as another crucial cellular defence system against toxic build-up of misfolded proteins. In contrast with basal autophagy that mediates non-selective, bulk clearance of misfolded proteins along with normal cellular proteins and organelles, the aggresome–autophagy pathway is increasingly recognized as a specialized type of induced autophagy that mediates selective clearance of misfolded and aggregated proteins under the conditions of proteotoxic stress. Recent evidence implicates PD-linked E3 ligase parkin as a key regulator of the aggresome–autophagy pathway and indicates a signalling role for Lys63-linked polyubiquitination in the regulation of aggresome formation and autophagy. The present review summarizes the current knowledge of the aggresome–autophagy pathway, its regulation by parkin-mediated Lys63-linked polyubiquitination, and its dysfunction in neurodegenerative diseases.

Download Full-text