scholarly journals Russell body inducing threshold depends on the variable domain sequences of individual human IgG clones and the cellular protein homeostasis

2012 ◽  
Vol 1823 (10) ◽  
pp. 1643-1657 ◽  
Author(s):  
Janelle Stoops ◽  
Samantha Byrd ◽  
Haruki Hasegawa
Keyword(s):  
Cellular Protein ◽  
Variable Domain ◽  
Protein Homeostasis ◽  
Human Igg ◽  
Individual Human

scholarly journals Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Peter Tsvetkov ◽  
Marc L Mendillo ◽  
Jinghui Zhao ◽  
Jan E Carette ◽  
Parker H Merrill ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Cellular Protein ◽  
Fitness Cost ◽  
Survival Advantage ◽  
Protein Homeostasis ◽  
Proteotoxic Stress ◽  
Genome Wide ◽  
Regulatory Complex ◽  
Modest Reduction ◽  
Specific Inhibitors

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.

scholarly journals ER stress causes widespread protein aggregation and prion formation

2017 ◽  
Vol 216 (8) ◽  
pp. 2295-2304 ◽  
Author(s):  
Norfadilah Hamdan ◽  
Paraskevi Kritsiligkou ◽  
Chris M. Grant
Keyword(s):  
Protein Aggregation ◽  
Er Stress ◽  
Secretory Pathway ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

scholarly journals Chaperones and Proteostasis: Role in Parkinson’s Disease

Diseases ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 24 ◽  
Author(s):  
Neha Joshi ◽  
Atchaya Raveendran ◽  
Shirisha Nagotu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Three Dimensional ◽  
Cellular Protein ◽  
The Body ◽  
Dimensional Structure ◽  
Protein Homeostasis ◽  
Altered Expression ◽  
And Function ◽  
Related Proteins

Proper folding to attain a defined three-dimensional structure is a prerequisite for the functionality of a protein. Improper folding that eventually leads to formation of protein aggregates is a hallmark of several neurodegenerative disorders. Loss of protein homeostasis triggered by cellular stress conditions is a major contributing factor for the formation of these toxic aggregates. A conserved class of proteins called chaperones and co-chaperones is implicated in maintaining the cellular protein homeostasis. Expanding the body of evidence highlights the role of chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review.

scholarly journals Variable domain-linked oligosaccharides of a human monoclonal IgG: structure and influence on antigen binding

1999 ◽  
Vol 338 (2) ◽  
pp. 529-538 ◽  
Author(s):  
Haike LEIBIGER ◽  
Daniel WÜSTNER ◽  
Rolf-Dietrich STIGLER ◽  
Uwe MARX
Keyword(s):  
Consensus Sequence ◽  
Variable Region ◽  
Glycosylation Site ◽  
Exchange Chromatography ◽  
Variable Domain ◽  
Dimensional Structure ◽  
Computer Assisted ◽  
Antigen Binding ◽  
Fab Fragment ◽  
Human Igg

The variable-domain-attached oligosaccharide side chains of a human IgG produced by a human–human–mouse heterohybridoma were analysed. In addition to the conserved N-glycosylation site at Asn-297, an N-glycosylation consensus sequence (Asn-Asn-Ser) is located at position 75 in the variable region of its heavy chain. The antibody was cleaved into its antigen-binding (Fab) and crystallizing fragments. The oligosaccharides of the Fab fragment were released by digestion with various endo- and exoglycosidases and analysed by anion-exchange chromatography and fluorophore-assisted carbohydrate electrophoresis. The predominant components were disialyl- bi-antennary and tetra-sialyl tetra-antennary complex carbohydrates. Of note is the presence in this human IgG of oligosaccharides containing N-glycolylneuraminic acid and N-acetylneuraminic acid in the ratio of 94:6. Furthermore, we determined N-acetylgalactosamine in the Fab fragment of this antibody, suggesting the presence of O-linked carbohydrates. A three-dimensional structure of the glycosylated variable (Fv) fragment was suggested using computer-assisted modelling. In addition, the influence of the Fv-associated oligosaccharides of the CBGA1 antibody on antigen binding was tested in several ELISA systems. Deglycosylation resulted in a decreased antigen-binding activity.

scholarly journals New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Cheng Ji
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Er Stress ◽  
Liver Diseases ◽  
Cell Cycle Progression ◽  
Alcohol Exposure ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Lipid Species

Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also in vivo  in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer.

scholarly journals Ribosome collision sensor Hel2 recognizes mistargeting secretory ribosome-nascent chain complexes

2020 ◽  
Author(s):  
Yoshitaka Matsuo ◽  
Toshifumi Inada
Keyword(s):  
Secretory Pathway ◽  
Signal Recognition Particle ◽  
Physiological Role ◽  
Cellular Protein ◽  
Ribosome Profiling ◽  
Secretory Proteins ◽  
Protein Homeostasis ◽  
Chain Complexes ◽  
Nascent Chain ◽  
Endogenous Substrates

SummaryRibosome collision due to translational stalling is recognized as a problematic event in translation by E3 ubiquitin ligase Hel2, leading to non-canonical subunit dissociation followed by targeting of the faulty nascent peptides for degradation. Although Hel2-mediated quality control greatly contributes to maintaining cellular protein homeostasis, its physiological role in dealing with endogenous substrates remains unclear. This study utilized genome-wide analysis, based on selective ribosome profiling, to survey the endogenous substrates for Hel2. This survey revealed that Hel2 preferentially binds to the pre-engaged secretory ribosome-nascent-chain complexes (RNCs), which translate upstream of targeting signals. Notably, Hel2 recruitment into secretory RNCs was elevated under signal recognition particle (SRP)-deficient conditions. Moreover, the mitochondrial defects caused by insufficient SRP were enhanced by hel2 deletion, along with the mistargeting of secretory proteins into mitochondria. Collectively, these findings provide novel insights into risk management in the secretory pathway that maintains cellular protein homeostasis.

scholarly journals How to design an optimal sensor network for the unfolded protein response

2018 ◽  
Vol 29 (25) ◽  
pp. 3052-3062 ◽  
Author(s):  
Wylie Stroberg ◽  
Hadar Aktin ◽  
Yonatan Savir ◽  
Santiago Schnell
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cellular Protein ◽  
Protein Accumulation ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
Stress Sensing ◽  
Coarse Model ◽  
The Unfolded Protein Response ◽  
Protein Response

Cellular protein homeostasis requires continuous monitoring of stress in the endoplasmic reticulum (ER). Stress-detection networks control protein homeostasis by mitigating the deleterious effects of protein accumulation, such as aggregation and misfolding, with precise modulation of chaperone production. Here, we develop a coarse model of the unfolded protein response in yeast and use multi-objective optimization to determine which sensing and activation strategies optimally balance the trade-off between unfolded protein accumulation and chaperone production. By comparing a stress-sensing mechanism that responds directly to the level of unfolded protein in the ER to a mechanism that is negatively regulated by unbound chaperones, we show that chaperone-mediated sensors are more efficient than sensors that detect unfolded proteins directly. This results from the chaperone-mediated sensor having separate thresholds for activation and deactivation. Finally, we demonstrate that a sensor responsive to both unfolded protein and unbound chaperone does not further optimize homeostatic control. Our results suggest a strategy for designing stress sensors and may explain why BiP-mitigated ER stress-sensing networks have evolved.

scholarly journals Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

2018 ◽  
Vol 399 (10) ◽  
pp. 1215-1221 ◽  
Author(s):  
Unekwu M. Yakubu ◽  
Kevin A. Morano
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Recent Progress ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor

Abstract Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network.

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