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GCN2 Adapts Protein Synthesis to Scavenging-Dependent Growth

ABSTRACT: Compared protein synthesis in Gcn2 WT vs Gcn2 KO murine PDAC cells (KRPC) in amino acid-replete or leucine-free media.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Pancreatic Ductal Adenocarcinoma

SUBMITTER: Michel Nofal

LAB HEAD: Josh Rabinowitz

PROVIDER: PXD028143 | Pride | 2022-10-13

REPOSITORIES: Pride

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			Action	DRS
	TGR_07780.raw	Raw
	TGR_07780_202010_All24_Rescue_3_wMeera_2.tgz	Other
	TGR_07781.raw	Raw
	TGR_07781_202010_All24_Rescue_3_wMeera_2.tgz	Other
	TGR_07782.raw	Raw

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Publications

GCN2 adapts protein synthesis to scavenging-dependent growth.

Nofal Michel M Wang Tim T Yang Lifeng L Jankowski Connor S R CSR Hsin-Jung Li Sophia S Han Seunghun S Parsons Lance L Frese Alexander N AN Gitai Zemer Z Anthony Tracy G TG Wühr Martin M Sabatini David M DM Rabinowitz Joshua D JD

Cell systems 20211026 2

Pancreatic cancer cells with limited access to free amino acids can grow by scavenging extracellular protein. In a murine model of pancreatic cancer, we performed a genome-wide CRISPR screen for genes required for scavenging-dependent growth. The screen identified key mediators of macropinocytosis, peripheral lysosome positioning, endosome-lysosome fusion, lysosomal protein catabolism, and translational control. The top hit was GCN2, a kinase that suppresses translation initiation upon amino aci ...[more]

PMID: 34706266

Similar Datasets

GCN2 adapts the proteome to scavenging-dependent growth

Project description:We report the transcriptional and translational changes that occur upon leucine deprivation +/- GCN2.

2020-05-25 | GSE151118 | GEO

Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

Project description:We analyzed the transcriptomes of Wild-type and GCN2-deficient mouse embryonic stem cells after 3h of arginine or leucine starvation.

2024-01-01 | GSE195470 | GEO

GCN2 suppresses TOP mRNA translation via LARP1

Project description:La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine tract (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5’TOP motif, resulting in the displacement of the eIF4E complex from TOP mRNAs. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. GCN2 inhibits TOP mRNA translation via ATF4-dependent transcriptional induction of LARP1 mRNAs and GCN1-mediated recruitment of LARP1 to stalled ribosomes. We performed ATF4 ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.

2022-08-31 | GSE166590 | GEO

The amino acid sensor GCN2 controls red blood cell life cycle and iron metabolism through regulation of tissue resident macrophages

Project description:GCN2 (General Control Nonderepressible 2) is a serine/threonine-protein kinase that controls mRNA translation in response to amino acid availability. Here we show that production and clearance of erythrocytes are controlled by GCN2. Our data highlight the importance of tissue-resident macrophages as the primary cell type mediating this effect. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2-/-) mice displayed resistance to anemia as compared to wild-type (GCN2+/+) mice. GCN2-/- liver macrophages display defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2-/- cells indicates that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating RBC clearance and iron recycling. We performed NRF2 (Nfe2l2) ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation.

2022-12-01 | GSE188460 | GEO

Eukaryotic Ribosome GCN2 interaction Hydrogen/Deuterium Exchange Mass Spectrometry

Project description:General control nonderepressible 2 (GCN2) phosphorylates eIF2α, regulating translation in response to nutritional stress. Here, we show that mammalian ribosomes are potent GCN2 activators. Hydrogen/deuterium exchange–mass spectrometry (HDX-MS) showed GCN2 interacting with domain II of the uL10 P-stalk protein. The P-stalk is a uL10/P12/P22 pentameric complex that is part of the ribosomal GTPase-associated center. Recombinant human P-stalk greatly stimulates GCN2. Both domain II of uL10 and the C-terminal tails of P1 and P2 are necessary for maximal GCN2 activation. On actively translating ribosomes, the C-terminal tails of P1 and P2 are sequestered by elongation factors, suggesting P-stalk availability could link translational stress to GCN2 activation.

2019-05-24 | PXD013051 | Pride

GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency

Project description:Disruptions in circadian rhythms are associated with increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole-body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24 h feeding fasting cycle. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a Control or leucine-devoid diet (LeuD) for 8-days in total darkness. On the last day, blood and livers were collected at circadian time (CT) 3 and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched chain amino acid concentrations (r2=0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillation in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Further, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole-body metabolism.

2024-08-27 | GSE262319 | GEO

Selective control of metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae

Project description:When eukaryotic cells are deprived of amino acids, uncharged tRNAs accumulate and activate the conserved GCN2 protein kinase. We examine how yeast growth and tRNA charging or aminoacylation is affected during amino acid depletion in the presence and absence of GCN2. tRNA charging is measured using a microarray technique which allows for simultaneous measurement of all cytosolic tRNAs. A fully prototrophic and its isogenic GCN2 deletion strain were used. We measured relative tRNA charging levels in yeast strains with an intact and deleted GCN2.

2010-08-01 | E-GEOD-22452 | biostudies-arrayexpress

ISR pathway activation signatures in MEFs: GCN2 and PERK

Project description:In response to different cellular stressors, the ISR kinases, PERK, PKR, HRI and GCN2, activate downstream transcriptional programs. While the core ISR transcription program is well characterized, markers that are specific to each individual ISR kinase activation pathway are not known. To identify markers that are induced by PERK or GCN2, but not the other ISR kinases, we subjected WT, GCN2-/-, and PERK-/- MEFs to amino acid starvation (RPMI 1640 SILAC -Lys -Arg) or Thapsigargin (200nM) treatment for 6 hours to activate the GCN2 and PERK pathways, respectively and performed RNA sequencing.

2022-07-01 | GSE179559 | GEO

Transcriptional responses of wild-type and Gcn2-/- Th17 cells to halofuginone and rapamycin

Project description:This study was designed to evaluate similarities and differences between transcriptional responses of developing Th17 cells to the prolyl-tRNA synthetase inhibitor, halofuginone, and the mTOR inhibitor, rapamycin. Further comparisons between wild-type and Gcn2-/- Th17 cells allow for investigation into which gene modules regulated by halofuginone or rapamycin treatment require Gcn2. Murine CD4+ CD25- T cells were magnetically isolated from wild-type or Gcn2-/- T cells. These cells were activated through anti-CD3/ anti-CD28 antibodies and polarized into Th17 cells using TGFb plus IL-6. 10 nM halofuginone, 10 nM rapamycin, or vehicle control (DMSO) were added to cultures at the time of activation. Cells were harvested at 4, 18, or 72 hours post-activation and differentiation. RNA was isolated from each sample and used for microarray analysis. Each culture condition and time-point was repeated twice in independent experiments using cells isolated from different wild-type or Gcn2-/- mice. Vehicle versus halofuginone, vehicle versus rapamycin, halofuginone versus rapamycin. Gcn2-/- versus wild-type T cells treated with vehicle, halofuginone, or rapamycin.

2014-05-29 | E-GEOD-47478 | biostudies-arrayexpress

Global Phosphoproteomics Pinpoints Uncharted Gcn2-Mediated Modes of Translational Control

Project description:To identify new Gcn2 target proteins, we performed a set of Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based quantitative phosphoproteomics experiments, in which we compared WT cells to gcn2∆ and sui2S52A cells (n=3), all treated, or not, with rapamycin, which has previously been shown to stimulate eIF2alpha phosphorylation by Gcn2.

2021-03-22 | PXD021109 | Pride

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