Role of ERN2/IRE1b in mediating unfolded protein response to ER stress
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205721 | GEO | 2022/09/20
REPOSITORIES: GEO
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Project description:Autophagy is a conserved process in eukaryotes that contributes to cell survival in response to stress. Previously, we found that ER stress induces autophagy in a manner dependent upon IRE1b, an ER membrane-associated factor involved in the splicing of bZIP60 mRNA. IRE1 is a dual protein kinase and ribonuclease, and here we studied the involvement of the protein kinase catalytic domain, nucleotide binding and RNase domains of IRE1b in activating autophagy. Autophagy was assessed by quantifying the numbers of autophagosomes in transgenic Arabidopsis seedlings bearing mutations in the various IRE1b domains. The results showed that nucleotide binding and RNase activity of IRE1b are required for ER stress-mediated autophagy. The RNase activity is involved in IRE1b’s mRNA splicing function, but its principal splicing target, bZIP60, is not involved in IRE1b’s activation of autophagy. We therefore considered other roles for IRE1b in the activation of autophagy. Clustering of ER localized IRE1b-YFP was observed when seedlings were subjected to ER stress, and so we investigated whether IRE1b clustering induced autophagy. However, the RNase knockout mutation in IRE1b still undergoes clustering, suggesting that IRE1b clustering does not induce autophagy. In response to ER stress, the RNase of IRE1 has been found to engage in another activity called Regulated Ire1-Dependent Decay of Messenger RNA (RIDD), which is the promiscuous degradation of other mRNA in response to ER stress. By analyzing the RNA-seq data, 12 RIDD target genes were picked up for testing their role in inhibiting autophagy, and glucosidase 21 and peroxidase 14 are proved to be degraded to support the induction of autophagy by ER stress.
2018-03-31 | GSE99576 | GEO
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 purpose of this study was to understand how the epithelial specific ER stress sensor ERN2/IRE1b contributes to goblet cell development in reseponse to gut microbes.
2022-09-20 | GSE205701 | GEO
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.
2011-02-17 | GSE27349 | GEO
Project description:We compared gene and protein expression profiles in cells challenged with ER stress-inducing drugs or expressing model polypeptides. Drugs titration to limit up-regulation of the endogenous ER stress reporters BiP/HSPA5 and HERP/HERPUD1 to levels comparable to luminal accumulation of unfolded proteins substantially reduced the amplitude of transcriptional and translational responses.
2018-02-16 | GSE108346 | GEO
Project description:The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation are unclear, including which pathways contribute to the phenotype in each organ. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver, but not the kidney; while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.
2017-06-23 | MTBLS472 | MetaboLights
Project description:The Unfolded Protein Response (UPR) is activated in plants in response to ER stress and plays an important role in mitigating stress damage. We have analyzed an ire1a ire1b bzip17 triple mutant in Arabidopsis with defects in stress signaling and found that the mutant is also impaired in vegetative plant growth under conditions without externally applied stress. This raises the question as to whether the UPR functions in plant development in same manner as it does in responding to stress. bZIP17 is an ER-associated membrane transcription factor that is mobilized to the nucleus in response to stress. Through the analysis of a mobilization defective bZIP17 mutant, we found that bZIP17 must be capable of mobilization to support normal plant development. Likewise, through the analysis of ire1 mutants, we found that protein kinase and ribonuclease activities of IRE1 must be functional to support normal development. These findings demonstrate that the UPR is active, albeit at low levels, during unstressed conditions, and that these activities are required for normal development.
2019-04-17 | GSE120672 | GEO
Project description:Unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in acromegaly
| PRJNA643979 | ENA
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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2013-03-25 | BIOMD0000000446 | BioModels
Project description:The stress sensors ATF6, IRE1 and PERK monitor deviations from homeostatic conditions in the endoplasmic reticulum (ER), a protein biogenesis compartment of eukaryotic cells. Their activation elicits unfolded protein responses (UPR) to re-establish proteostasis. UPR have been extensively investigated in cells exposed to chemicals that activate ER stress sensors by perturbing calcium, sugars or redox homeostasis. Cell responses to variations in luminal load with unfolded proteins are, in contrast, poorly characterized. Here, we compared gene and protein expression profiles in cells challenged with ER stress-inducing drugs or expressing model polypeptides. Drugs titration to limit up-regulation of the endogenous ER stress reporters BiP/HSPA5 and HERP/HERPUD1 to levels comparable to luminal accumulation of unfolded proteins substantially reduced the amplitude of transcriptional and translational responses. Nevertheless, these remained pleiotropic and failed to recapitulate responses to ER load with unfolded proteins, which induced a limited subset of genes participating in a chaperone complex that binds unfolded chains.
2018-02-16 | PXD008529 | Pride