scholarly journals ER-associated degradation: Protein quality control and beyond

2014 ◽  
Vol 204 (6) ◽  
pp. 869-879 ◽  
Author(s):  
Annamaria Ruggiano ◽  
Ombretta Foresti ◽  
Pedro Carvalho
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Degradation ◽  
Control Systems ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Secretory Proteins ◽  
Toxic Species ◽  
Cellular Factors

Even with the assistance of many cellular factors, a significant fraction of newly synthesized proteins ends up misfolded. Cells evolved protein quality control systems to ensure that these potentially toxic species are detected and eliminated. The best characterized of these pathways, the ER-associated protein degradation (ERAD), monitors the folding of membrane and secretory proteins whose biogenesis takes place in the endoplasmic reticulum (ER). There is also increasing evidence that ERAD controls other ER-related functions through regulated degradation of certain folded ER proteins, further highlighting the role of ERAD in cellular homeostasis.

scholarly journals The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components

2015 ◽  
Vol 60 (3) ◽  
pp. 1438-1449 ◽  
Author(s):  
Shriya Raj ◽  
Karthik Krishnan ◽  
David S. Askew ◽  
Olivier Helynck ◽  
Peggy Suzanne ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Antifungal Compound ◽  
Content Type ◽  
Enhanced Sensitivity ◽  
Fungal Organisms

In a search for new antifungal compounds, we screened a library of 4,454 chemicals for toxicity against the human fungal pathogenAspergillus fumigatus. We identified sr7575, a molecule that inhibits growth of the evolutionary distant fungiA. fumigatus,Cryptococcus neoformans,Candida albicans, andSaccharomyces cerevisiaebut lacks acute toxicity for mammalian cells. To gain insight into the mode of inhibition, sr7575 was screened against 4,885S. cerevisiaemutants from the systematic collection of haploid deletion strains and 977 barcoded haploid DAmP (decreased abundance by mRNA perturbation) strains in which the function of essential genes was perturbed by the introduction of a drug resistance cassette downstream of the coding sequence region. Comparisons with previously published chemogenomic screens revealed that the set of mutants conferring sensitivity to sr7575 was strikingly narrow, affecting components of the endoplasmic reticulum-associated protein degradation (ERAD) stress response and the ER membrane protein complex (EMC). ERAD-deficient mutants were hypersensitive to sr7575 in bothS. cerevisiaeandA. fumigatus, indicating a conserved mechanism of growth inhibition between yeast and filamentous fungi. Although the unfolded protein response (UPR) is linked to ERAD regulation, sr7575 did not trigger the UPR inA. fumigatusand UPR mutants showed no enhanced sensitivity to the compound. The data from this chemogenomic analysis demonstrate that sr7575 exerts its antifungal activity by disrupting ER protein quality control in a manner that requires ERAD intervention but bypasses the need for the canonical UPR. ER protein quality control is thus a specific vulnerability of fungal organisms that might be exploited for antifungal drug development.

Protein quality control at the endoplasmic reticulum

2016 ◽  
Vol 60 (2) ◽  
pp. 227-235 ◽  
Author(s):  
Kathleen McCaffrey ◽  
Ineke Braakman
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Bond Formation ◽  
Protein Quality Control ◽  
Secretory Proteins ◽  
Protein Quality Control System ◽  
And Function ◽  
Extracellular Environment

The ER (endoplasmic reticulum) is the protein folding ‘factory’ of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ER hosts a unique PQC (protein quality control) system that allows specialized modifications such as glycosylation and disulfide bond formation essential for the correct folding and function of many secretory proteins. It is also the major checkpoint for misfolded or aggregation-prone proteins that may be toxic to the cell or extracellular environment. A failure of this system, due to aging or other factors, has therefore been implicated in a number of serious human diseases. In this article, we discuss several key features of ER PQC that maintain the health of the cellular secretome.

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

2018 ◽  
Vol 87 (1) ◽  
pp. 751-782 ◽  
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.

Positive contribution of ERdj5/JPDI to endoplasmic reticulum protein quality control in the salivary gland

2009 ◽  
Vol 425 (1) ◽  
pp. 117-128 ◽  
Author(s):  
Akira Hosoda ◽  
Mio Tokuda ◽  
Ryoko Akai ◽  
Kenji Kohno ◽  
Takao Iwawaki
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Salivary Gland ◽  
Er Stress ◽  
Knockout Mice ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Whole Body ◽  
Secretory Proteins ◽  
Positive Contribution

In eukaryotic cells, most membrane and secretory proteins are modified post-translationally in the ER (endoplasmic reticulum) for correct folding and assembly. Disulfide-bond formation is one of the important modifications affecting folding and is catalysed by the PDI (protein disulfide isomerase) family proteins. ERdj5 [also known as JPDI (J-domain-containing PDI-like protein)] is a member of the PDI family proteins and has been reported to act as a reductase in ERAD (ER-associated degradation). However, the role of ERdj5 at the whole-body level remains unclear. Therefore in the present study we generated ERdj5-knockout mice {the mouse gene of ERdj5 is known as Dnajc10 [DnaJ (Hsp40) homologue, subfamily C, member 10]} and analysed them. Although ERdj5-knockout mice were viable and healthy, the ER stress response was activated in the salivary gland of the knockout mice more than that of control mice. Furthermore, in ERdj5-knockout cells, the expression of exogenous ERdj5 mitigated the ER stress caused by overproduction of α-amylase, which is one of the most abundant proteins in saliva and has five intramolecular disulfide bonds. This effect was dependent on the thioredoxin-like motifs of ERdj5. Thus we suggest that ERdj5 contributes to ER protein quality control in the salivary gland.

scholarly journals Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation

2021 ◽  
Vol 8 ◽  
Author(s):  
Diego Ruano
Keyword(s):  
Quality Control ◽  
Control Systems ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Normal Aging ◽  
Cellular Protein ◽  
World Population ◽  
Age Related

Aging is a biological and multifactorial process characterized by a progressive and irreversible deterioration of the physiological functions leading to a progressive increase in morbidity. In the next decades, the world population is expected to reach ten billion, and globally, elderly people over 80 are projected to triple in 2050. Consequently, it is also expected an increase in the incidence of age-related pathologies such as cancer, diabetes, or neurodegenerative disorders. Disturbance of cellular protein homeostasis (proteostasis) is a hallmark of normal aging that increases cell vulnerability and might be involved in the etiology of several age-related diseases. This review will focus on the molecular alterations occurring during normal aging in the most relevant protein quality control systems such as molecular chaperones, the UPS, and the ALS. Also, alterations in their functional cooperation will be analyzed. Finally, the role of inflammation, as a synergistic negative factor of the protein quality control systems during normal aging, will also be addressed. A better comprehension of the age-dependent modifications affecting the cellular proteostasis, as well as the knowledge of the mechanisms underlying these alterations, might be very helpful to identify relevant risk factors that could be responsible for or contribute to cell deterioration, a fundamental question still pending in biomedicine.

Abstract 30: Nub1l Suppresses Neddylation And Enhances Misfolded Protein Clearance In Cardiomyocytes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Huabo Su ◽  
Jie Li ◽  
Wenxia Ma ◽  
Ning Hou ◽  
Faqian Li
Keyword(s):  
Quality Control ◽  
Protein Degradation ◽  
Cardiac Disease ◽  
Protein Modification ◽  
Protein Quality ◽  
Ischemia Reperfusion ◽  
Protein Quality Control ◽  
Misfolded Protein ◽  
Dependent Manner

Protein modification by ubiquitin (Ub) or Ub-like proteins such as NEDD8 (neddylation) constitutes a fundamental regulatory mechanism of protein function. In contrast to well-recognized role of Ub in protein degradation, little is known about the role of NEDD8 in protein quality control. We have previously revealed that CM-restricted inactivation of deneddylation, a process that removes NEDD8 from modified proteins, accumulates neddylated proteins and impairs proteasomal and autophagic proteolysis. Here we report that proteasome inhibitors, simulated ischemia/reperfusion and H2O2 significantly increase NEDD8 conjugates in cardiomyocytes (CMs). Immunoprecipitation analysis reveals mixed modification of these proteins by Ub and NEDD8. Expression of NEDD8 but not the conjugation-deficient mutant increases neddylated proteins and accumulates a proteasome surrogate substrate GFPu in a dose-dependent manner, suggesting that excessive neddylation disrupts proteasomal proteolysis. We further targets to NUB1L, a UBL (Ub-like domain)-UBA (Ub associating domain) family protein that was shown to negatively regulate neddylation. NUB1L expression markedly reduces free NEDD8 by promoting its degradation, and abrogates proteasome inhibition-induced neddylation in CMs. Suppression of neddylation by NUB1L expression enhances GFPu degradation at baseline, and attenuates GFPu accumulation upon sI/R and H2O2 treatment. Furthermore, NUB1L expression promotes, while down-regulation of NUB1L impairs, the clearance of a bona fide misfolded protein in CMs. NUB1L expression also ameliorates proteotoxic stress- and sI/R-induced CM injury. Finally, increased NEDD8 conjugates are evident in the mouse hearts of a number of cardiac disease models as well as in human failing hearts. Together, our findings suggest that excessive neddylation disrupts protein quality control and that antagonizing neddylation by NUB1L promotes misfolded protein degradation. Targeting neddylation/NUB1L could be a novel therapeutic strategy for prevention and treatment of insufficient protein quality control-associated cardiac disease.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

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