Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68718 | GEO | 2015/05/12
SECONDARY ACCESSION(S): PRJNA283493
REPOSITORIES: GEO
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Project description:Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress. 24 total samples. One sample represents one mouse. Three samples were analyzed from the following groups: Lrh-1 f/f (control littermates) treated with vehicle, Lrh-1 f/f treated with tunicamycin (TM; 1mg/kg BW for 24h), Lrh-1 f/f treated with tunicamycin and DLPC (100mg/kg BW 4x), Lrh-1 f/f treated with tunicamycin and vehicle for DLPC, Lrh-1 liver-specific KO mice (LKO) treated with vehicle, Lrh-1 LKO treated with tunicamycin, and Lrh-1 LKO treated with tunicamycin and DLPC, Lrh-1 LKO treated with tunicamycin and vehicle for DLPC
2015-05-12 | E-GEOD-68718 | biostudies-arrayexpress
Project description:Adverse environmental and pathophysiological situations can overwhelm the biosynthetic capacity of the endoplasmic reticulum (ER), igniting a potentially lethal condition known as ER stress. ER stress results in growth reduction and the activation of a conserved cytoprotective signaling cascade, the unfolded protein response (UPR), to mitigate ER stress. As ER stress subsides, growth is resumed; however, despite a pivotal role of the UPR in growth restoration, the underlying mechanisms are yet unknown. To discover these, we undertook a genomics approach and mined the gene reprogramming roles of the two critical and conserved UPR modulators, basic leucine zipper28 (bZIP28) and bZIP60 in ER stress resolution. Through a coexpression-based network modeling and experimental validation, we identified key responsive genes acting downstream of the UPR bZIP-transcription factors (bZIP-TF), and demonstrated their roles in organ growth during recovery from ER stress. Our analyses have also set up a novel pipeline for functional gene discovery in ER stress resolution with broad applicability across multicellular eukaryotes.
2021-12-20 | GSE146723 | GEO
Project description:Perturbing ER homeostasis activates stress programs collectively called the unfolded protein response (UPR). The UPR enhances production of ER-resident chaperones and enzymes to reduce the burden of misfolded proteins. Upon resolution of ER stress, excess ER material is removed by ill-defined, selective autophagic programs. Here, using biochemical and cell-based essays, we identify a novel ER-resident autophagy receptor, Sec62, which is activated during recovery from ER stress to selectively deliver ER fragments to the autolysosomal system for clearance. Quantitative mass spectrometry analyses of autolysosomal fractions upon selective inactivation of the Sec62-regulated pathway inform on the selectivity of Sec62-regulated ER-phagy.
2016-10-11 | PXD003961 | Pride
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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2024-09-02 | BIOMD0000000446 | BioModels
Project description:Perturbation of tissue homeostasis accompanies a diversity of inflammatory pathologies and imposes metabolic constraints at the cellular level that elicit ER stress, protein misfolding, and cell death. In response to ER stress, cells initiate the unfolded protein response (UPR), which determines divergent cell fate decisions, either promoting recovery of ER proteostasis and cell survival or triggering programmed cell death. However, the mechanisms by which the UPR transitions from the adaptive to terminal state are not fully understood. To discover novel UPR pathway regulators that influence the outcome of cellular ER stress responses, we performed genome-scale genetic perturbations. Our genome-wide screens revealed that distinct sets of genes regulate UPR activity and maintenance of ER homeostasis. This expansive dataset provides a rich resource that can be leveraged to elucidate signaling crosstalk during ER stress and discover novel UPR regulators.
2021-02-17 | GSE146841 | GEO
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:All animals must maintain genome and proteome integrity, especially when experiencing endogenous or exogenous stress. To cope, organisms have evolved sophisticated and conserved response systems: unfolded protein responses (UPRs) ensure proteostasis while the DNA damage response (DDR) maintains genome integrity. Emerging evidence suggests that UPRs and DDRs crosstalk, but the extent of crosstalk remains poorly understood. Here, we demonstrate that inactivation of the DNA primases pri-1 and pri-2, which synthesize RNA primers at replication forks and whose inactivation causes DNA damage, activates the UPR of the endoplasmic reticulum (UPR-ER) in Caenorhabditis elegans, with especially strong activation in the germline. We observed activation of both the inositol-requiring-enzyme 1 (ire-1) and the protein kinase RNA-like ER kinase (PEK-1) branches of the UPR-ER. Interestingly, activation of the UPR-ER output gene hsp-4/BiP was partially independent of its canonical activators, ire-1 and xbp-1, and instead required the third branch of the UPR-ER, atf-6, suggesting functional redundancy. We further found that primase depletion specifically induces the UPR-ER, but not the mechanistically distinct cytosolic or mitochondrial UPRs, suggesting that primase inactivation causes compartment-specific rather than global stress. Functionally, loss of ire-1 or pek-1 sensitized animals to replication stress caused by hydroxyurea. Finally, transcriptome analysis of pri-1 embryos revealed several deregulated processes that could cause UPR-ER activation, including protein glycosylation, calcium signaling, and fatty acid desaturation. Together, our data show that the UPR-ER, but not other UPRs, responds to replication fork stress and that the UPR-ER is required to alleviate this stress.
2024-01-17 | GSE225569 | GEO
Project description:We tracked the gene expression events following treatment of maize seedlings with the endoplasmic reticulum (ER) stress agent tunicamycin. ER stress elicits the unfolded protein response (UPR) and when plants are faced with persistent stress, the UPR transitions from an adaptive or cell survival phase to programmed cell death.
2018-05-30 | GSE111250 | GEO
Project description:Perturbation of tissue homeostasis accompanies a diversity of inflammatory pathologies and imposes metabolic constraints at the cellular level that elicit ER stress, protein misfolding, and cell death. In response to ER stress, cells initiate the unfolded protein response (UPR), which determines divergent cell fate decisions, either promoting recovery of ER proteostasis and cell survival or triggering programmed cell death. However, the mechanisms by which the UPR transitions from the adaptive to terminal state are not fully understood. Here, we leverage single-cell genomics to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the intestinal epithelium. We recovered the terminal-UPR signature, which dictates adaptation versus programmed cell death in response to ER stress.
2021-02-17 | GSE149633 | GEO
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