Expression levels in immortalized B cells from unrelated individuals and twins undergoing ER stress
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE19519 | GEO | 2010/03/30
SECONDARY ACCESSION(S): PRJNA122347
REPOSITORIES: GEO
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Project description:The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called âER stressâ which induces the unfolded protein response (UPR) which is a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis in the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B-cells and then measured gene expression at 10 time-points. We followed up those results by studying cells from 60 unrelated people. We rediscovered genes that were known to play a role in ER stress response and uncovered several thousand genes that are not known to be involved. Two of these are VLDLR and INHBE which showed significant increase in expression following ER stress in B-cells and in primary fibroblasts. To study the links between unfolded protein response and disease susceptibility, we identified ER stress responsive genes that are associated with human diseases and assessed individual differences in ER stress response. Many of the UPR genes are associated with Mendelian disorders such as Wolfram syndrome and complex human diseases including amyotrophic lateral sclerosis and diabetes. Data from two independent samples showed extensive individual variability in ER stress response. Additional analyses with monozygotic twins revealed significant correlations within twin pairs in their responses to ER stress thus showing evidence for heritable variation among individuals. These results have implications for basic understanding of ER function and its role in disease susceptibility. Keywords: array-based gene expression We measured gene expression levels in immortalized B cells from members of 60 unrelated CEPH-Utah grandparents. Each individual was treated for 8 hours with either DMSO or with 4 ug/ml of tunicamycin. Gene expression was measured to identify tunicamycin-responsive genes. To assess whether there is a genetic component to the individual variation in gene expression response to ER stress, we used microarrays to measure expression of genes in 26 monozygotic twin pairs treated with either DMSO or 500 nM thapsigargin for 4 hours.
2010-04-08 | E-GEOD-19519 | biostudies-arrayexpress
Project description:Erguler2013 - Unfolded protein stress response
The model investigates the mechanism by which UPR (unfolded protein response) outcome switches between survival and death.
This model is described in the article:
A mathematical model of the unfolded protein stress response reveals the decision mechanism for recovery, adaptation and apoptosis.
Erguler K, Pieri M, Deltas C.
BMC Syst Biol. 2013 Feb 21;7(1):16.
Abstract:
BACKGROUND: The unfolded protein response (UPR) is a major signalling cascade acting in the quality control ofprotein folding in the endoplasmic reticulum (ER). The cascade is known to play an accessory rolein a range of genetic and environmental disorders including neurodegenerative and cardiovasculardiseases, diabetes and kidney diseases. The three major receptors of the ER stress involved withthe UPR, i.e. IRE1a, PERK and ATF6, signal through a complex web of pathways to convey anappropriate response. The emerging behaviour ranges from adaptive to maladaptive depending on theseverity of unfolded protein accumulation in the ER; however, the decision mechanism for the switchand its timing have so far been poorly understood.
RESULTS:
Here, we propose a mechanism by which the UPR outcome switches between survival and death.We compose a mathematical model integrating the three signalling branches, and perform a comprehensivebifurcation analysis to investigate possible responses to stimuli. The analysis reveals threedistinct states of behaviour, low, high and intermediate activity, associated with stress adaptation, tolerance,and the initiation of apoptosis. The decision to adapt or destruct can, therefore, be understoodas a dynamic process where the balance between the stress and the folding capacity of the ER playsa pivotal role in managing the delivery of the most appropriate response. The model demonstratesfor the first time that the UPR is capable of generating oscillations in translation attenuation and theapoptotic signals, and this is supplemented with a Bayesian sensitivity analysis identifying a set ofparameters controlling this behaviour.
CONCLUSIONS:
This work contributes largely to the understanding of one of the most ubiquitous signalling pathwaysinvolved in protein folding quality control in the metazoan ER. The insights gained have direct consequenceson the management of many UPR-related diseases, revealing, in addition, an extended listof candidate disease modifiers. Demonstration of stress adaptation sheds light to how preconditioningmight be beneficial in manifesting the UPR outcome to prevent untimely apoptosis, and paves the wayto novel approaches for the treatment of many UPR-related conditions.
In the paper, PERKA refers to the amount of phosphorylated PERK monomer. However, it refers to the active complex in the model. The complex with the model parameterization is formed of 4 monomers (n=4). So, the value of PERKA should be multiplied by 4, in order to generate the figures in the paper (eg. Figure 12).
An additional parameter (tmr=10)) is used in the model. This parameter is not mentioned in the paper. The model values of kf(=10) and kr(=1) are not consistent with that of the paper (kf=100, kr=10, in the paper). However, this is corrected by the introduction of "tmr" in the model, which is multiplied with kf and kr to get the resulting values.
The term "tmr" was missing in the kinetic laws of the reactions reu7 and reu8, in the original model. This has been corrected as per the author's request.
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by: MODEL1302180000
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for published quantitative kinetic models
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2024-09-02 | BIOMD0000000446 | BioModels
Project description:We are currently studying how these information-carrying oligosaccharides are involved in cellular stress responses, particularly in human genetic diseases called Congenital Disorders Of Glycosylation in which oligosaccharide assembly is defective. We are interested in endoplasmic stress responses/unfolded protein responses. ER glycans and ER lectins are intimately involved in the folding of ER proteins. Therefore, ER lectins and ER glycosyltransferases may be controlled by these stress responses, to produce and/or recognize key glycans in the stress response. Our model system is the human dermal fibroblast. We have successfully calibrated the ER stress responses in these cells by determining the magnitudes of various stress effects (such as chaperone transcription) with different forms of ER stress. We are also completing a study in which activation the signaling molecules Ire1 and ATF6 are also calibrated. We prepared multiple identical aliquots of RNA from cells stressed under several of these calibrated conditions. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR): Study of the role of ER stress in the expression of genes for ER transferases and lectins that participate in ER folding and quality control using human skin fibroblasts. The UPR response in these cells has been calibrated using various readouts in response to different stresses: 1) 40 nM L-azetidine-2-carboxylate (AZC) 1 hour, 2) 0.2 mg/ml castanospermine, 24 hours, 3) 2 mM Dithiothreitol (DTT), 20 minutes, 4) 100nm Thapsigargin (TG), 30 minutes, 5) 5 ug/ml tunicamycin, 5 hours, 6) untreated control cells
2011-02-17 | E-GEOD-27349 | biostudies-arrayexpress
Project description:The accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes stress and induces the unfolded protein response (UPR) which is characterised in part by the transcriptional induction of genes involved in assisting protein folding. Translational responses to ER stress have been less well described and here we report on a genome-wide analysis of translational regulation in the response to the ER stress-inducing agent dithiothreitol (DTT) in Saccharomyces cerevisiae. Although the observed polysome profiles were similar under control and ER stress conditions microarray analysis identified transcipt-specific translational regulation. Genes with functions in ribosomal biogenesis and assembly were translationally repressed under ER stress. In contrast mRNAs for known UPR genes, including the UPR transcription factor HAC1, the ER-oxidoreductase ERO1 and the ER-associated protein degradation (ERAD) gene DER1 were enriched in polysomal fractions under ER stress conditions. In addition, we show that splicing of HAC1 mRNA is required for efficient ribosomal loading and that Gcn2p is required for normal HAC1 splicing, so shedding light on the role of this protein kinase in the UPR pathway. Experiment Overall Design: Polyribosomes were extracted from S. cerevisiae cells treated with 2 mM DTT or water (control), and fractionated according to ribosome loading. Following RNA purification from these fractions, for each sub-polysomal and polysomal RNA sample, fractions from three independent extracts per treatment (DTT/control) were pooled.
2008-06-11 | E-GEOD-10091 | biostudies-arrayexpress
Project description:The accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) causes stress and induces the unfolded protein response (UPR) which is characterised in part by the transcriptional induction of genes involved in assisting protein folding. Translational responses to ER stress have been less well described and here we report on a genome-wide analysis of translational regulation in the response to the ER stress-inducing agent dithiothreitol (DTT) in Saccharomyces cerevisiae. Although the observed polysome profiles were similar under control and ER stress conditions microarray analysis identified transcipt-specific translational regulation. Genes with functions in ribosomal biogenesis and assembly were translationally repressed under ER stress. In contrast mRNAs for known UPR genes, including the UPR transcription factor HAC1, the ER-oxidoreductase ERO1 and the ER-associated protein degradation (ERAD) gene DER1 were enriched in polysomal fractions under ER stress conditions. In addition, we show that splicing of HAC1 mRNA is required for efficient ribosomal loading and that Gcn2p is required for normal HAC1 splicing, so shedding light on the role of this protein kinase in the UPR pathway. Keywords: stress response, translational analysis
2008-01-07 | GSE10091 | GEO
Project description:Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER-mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an unprecedented role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.
2019-11-12 | PXD014890 | Pride
Project description:Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.
2020-04-24 | GSE131146 | GEO
Project description:Metabolic diseases are strongly associated with endoplasmic reticulum (ER) stress. Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage. However, escalating cellular UPR response weakens with age. Here, we show that 5-day-old Caenorhabditis elegans fed a bacteria diet with 2% glucose (high glucose diet, HGD-5) extend their lifespan while shortening the lifespan of 1-day-old (HGD-1) animals. We observed a metabolic shift in HGD-1 as glucose and fertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 extended the longevity of HGD-5 worms, while the ire-1 ablation drastically increased HGD-1 lifespan. Based on these observations, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.
2021-08-31 | GSE182981 | GEO
Project description:A data-entrained computational model for
testing the regulatory logic of the vertebrate unfolded protein
response
This model is described in the article:
A data-entrained
computational model for testing the regulatory logic of the
vertebrate unfolded protein response.
Diedrichs DR, Gomez JA, Huang CS,
Rutkowski DT, Curtu R.
Mol. Biol. Cell 2018 Apr; :
mbcE17090565
Abstract:
The vertebrate unfolded protein response (UPR) is
characterized by multiple interacting nodes among its three
pathways, yet the logic underlying this regulatory complexity
is unclear. To begin to address this issue, we created a
computational model of the vertebrate UPR that was entrained
upon and then validated against experimental data. As part of
this validation, the model successfully predicted the
phenotypes of cells with lesions in UPR signaling, including a
surprising and previously unreported differential role for the
eIF2? phosphatase GADD34 in exacerbating severe stress but
ameliorating mild stress. We then used the model to test the
functional importance of a feed-forward circuit within the
PERK/CHOP axis, and of cross-regulatory control of BiP and CHOP
expression. We found that the wiring structure of the UPR
appears to balance the ability of the response to remain
sensitive to ER stress yet also to be rapidly deactivated by
improved protein folding conditions. This model should serve as
a valuable resource for further exploring the regulatory logic
of the UPR.
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To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
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the public domain worldwide. Please refer to
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2024-09-02 | BIOMD0000000703 | BioModels
Project description:Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here we discovered that accumulation of unfolded/misfolded proteins selectively induces N6-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes CHOP mRNA decay through its 3’UTR N6-adenosine methylation (m6A) to inhibit its downstream pro-apoptotic target genes expression. UPR induces METTL14 expression through competing the HRD1-ERAD machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m6A pathways, the ERm6A pathway, for ER stress adaptation to proteotoxicity.
2021-09-30 | GSE185109 | GEO