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Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Adaptive Mitochondrial Remodeling in Perk-deficient Cells

ABSTRACT: Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Adaptive Mitochondrial Remodeling in Perk-deficient Cells

PROVIDER: PRJNA943278 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23814100_1.fastq.gz	Fastqsanger.gz
	SRR23814100_2.fastq.gz	Fastqsanger.gz
	SRR23814101_1.fastq.gz	Fastqsanger.gz
	SRR23814101_2.fastq.gz	Fastqsanger.gz
	SRR23814102_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Adaptive Mitochondrial Remodeling in Perk-deficient Cells

Project description:mRNA sequencing of WT or PERK-/- MEFs treated with the ISR activating compounds BtdCPU, Halofuginone, and Thapsigargin.

2023-09-09 | GSE227134 | GEO

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells.

Project description:The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.

| S-EPMC10029010 | biostudies-literature

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.

2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

2012-01-20 | GSE29929 | GEO

Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity

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Pharmacologic inhibition of EphB3 receptor kinase ameliorates EAE

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Integrated genetic and pharmacologic interrogation of rare cancers

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ISR target genes revealed by comprehensive microarray network study using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK

Project description:To identify the target genes of integrated stress reponse (ISR), we have employed whole genome microarray expression in MEF cells. ISR gene setimation under ER stress condition using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK MEF cells

2015-09-01 | E-GEOD-49598 | biostudies-arrayexpress

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Project description:Prevention or delay of autoimmune type 1 diabetes (T1D) onset is possible if molecular triggering events can be pharmacologically targeted. The integrated stress response (ISR) is activated during cellular stress to halt protein production and redirect energy towards cellular survival temporarily. We hypothesized that the activity of the ISR in the insulin-producing β cell during T1D becomes maladaptive and renders the cell prone to autoimmunity. We show that suppression of the ISR by using a novel inhibitor of the kinase PERK reverses the translation initiation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the unfolded protein response and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics analysis of islets from these mice shows a post-transcriptional increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-βH1 human β cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

2024-06-05 | GSE245004 | GEO

PERK-dependent gene expression programs of the acute and chronic cellular response to ER stress

Project description:The UPR (Unfolded Protein Response) is a well-orchestrated response to ER protein folding and processing overload, integrating both transcriptional and translational outputs. Its three arms in mammalian cells, the PERK translational response arm, together with the ATF6 and IRE1-mediated transcriptional arms, have been thoroughly investigated. Using ribosome footprint profiling, we performed a deep characterization of the gene expression programs involved in the acute and adaptive ER stress responses. We utilized MEFs (Mouse Embryonic Fibroblasts) treated with Thapsigargin for different durations, that were wither WT or PERK knockouts, to determine the role of PERK in the acute and chronic UPR. We characterized three major gene expression programs: acute induction, chronic induction, and repression, and found that they were all PERK dependent. All three programs were recapitulated in publicly available data and in NIH3T3 cells. While PERK -/- cells did not recapitulate these responses in the acute timepoints, late timepoints showed an extremely weak induction/repression, suggesting that the chronic responses in WT cells are largely PERK dependent as well. We found that most ER target proteins were significantly repressed; including transmembrane proteins, glycoproteins, and proteins with disulfide bonds. We further demonstrate the downregulation of cyclins, while the expression of the amino acid biosynthesis pathway was enhanced.

2019-03-20 | GSE118660 | GEO

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