Advanced genomics identifies growth effectors for proteotoxic ER stress recovery in Arabidopsis thaliana
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ABSTRACT:
ORGANISM(S): Arabidopsis thaliana
PROVIDER: GSE146723 | GEO | 2021/12/20
REPOSITORIES: GEO
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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
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.
2015-05-12 | GSE68718 | GEO
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
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2018-03-07 | GSE100371 | GEO
Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-β (TGF-β)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-β/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.
2016-01-15 | E-GEOD-70208 | biostudies-arrayexpress
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:We set out to generate transcriptional maps of chondrocyte UPR gene networks in vivo using two mouse models (Schmid and Cog) of Schmid chondrodysplasia, in order to define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy, thus providing insights into ER stress signaling and its impact on cartilage pathophysiology. Our data demonstrate that both models displayed similar unfolded protein responses (UPRs), involving activation of ER stress sensors Ire1 and Atf6 and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Moreover, we transcriptionally profiled the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones, in order to define the differentiation status of ER-stressed chondrocytes in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes.
2012-01-01 | GSE30628 | GEO
Project description:We set out to generate transcriptional maps of chondrocyte UPR gene networks in vivo using two mouse models (Schmid and Cog) of Schmid chondrodysplasia, in order to define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy, thus providing insights into ER stress signaling and its impact on cartilage pathophysiology. Our data demonstrate that both models displayed similar unfolded protein responses (UPRs), involving activation of ER stress sensors Ire1 and Atf6 and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Moreover, we transcriptionally profiled the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones, in order to define the differentiation status of ER-stressed chondrocytes in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. For the mutant hypertrophic zone gene expression profiling, the hypertrophic zone from one tibia from each of three two week old Schmid, wildtype (Schmid background), Cog, and wildtype (Cog background) mice was microdissected. In all cases, total RNA was extracted and amplified through two rounds of linear amplification, labelled with Cy3, and interrogated by microarray analysis using the Agilent 44K, mouse whole genome platform.
2012-01-01 | E-GEOD-30628 | biostudies-arrayexpress
Project description:Cells respond to endoplasmic reticulum (ER) stress through activation of signaling pathways such as the Unfolded Protein Response (UPR) which improve the ER folding environment capacity upon changes in misfolded protein burden. Small molecules termed chemical chaperones can attenuate the UPR under stress conditions and improve folding and trafficking of specific mutant proteins. One such compound is the bile acid tauroursodeoxycholic acid (TUDCA). Despite promising results in multiple models of protein folding diseases, TUDCA’s mechanism of action remains unclear. To better define how TUDCA attenuate ER stress, we leveraged the genetically tractable budding yeast, S. cerevisiae. Consistent with properties described for TUDCA, we found it significantly improves growth of yeast subjected to ER stress caused by the N-glycosylation inhibitor tunicamycin (Tm) independently of activity of the UPR. In addition to other data, transcriptomics of strains treated with TUDCA link its ability to resuce Tm-induced stress with cell wall remodeling.
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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