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Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress

ABSTRACT: Here we report Total RNA seq and RiboSeq on MEF cells treated with halofuginone. Halofuginone is a competitive inhibitor of the Prolyl-tRNA synthetase that results in an accumulation of uncharged Prolyl-tRNA upon treatment that leads to an activation of the protein kinase Gcn2.

ORGANISM(S): Mus musculus

PROVIDER: GSE156850 | GEO | 2021/05/26

REPOSITORIES: GEO

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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.

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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.

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

2014-05-29 | GSE47478 | GEO

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

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Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions

Project description:Diverse environmental insults induce the integrated stress response (ISR), which features eIF2 phosphorylation and translational control that serves to restore protein homeostasis. The eIF2 kinase GCN2 is a first responder in the ISR that is activated by amino acid depletion and other unrelated stresses. Two processes are suggested to trigger an ordered process of GCN2 activation during stress: GCN2 monitoring stress via accumulating uncharged tRNAs or by stalled and colliding ribosomes. Our results suggest that while ribosomal collisions are indeed essential for GCN2 activation in response to translational elongation inhibitors, conditions that trigger deacylation of tRNAs activate GCN2 via its direct association with affected tRNAs. Both process require the GCN2 regulatory domain related to histidyl tRNA synthetases. GCN2 activation by UV irradiation features lowered amino acids and increased uncharged tRNAs and ribosome collisions are dispensable. We conclude that there are multiple mechanisms that activate GCN2 during diverse stresses.

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The HisRS-like domain of GCN2 is a pseudoenzyme that can bind uncharged tRNA - HX-MS Data

Project description:GCN2 is a stress response kinase that phosphorylates the translation initiation factor eIF2to inhibit general protein synthesis when activated by uncharged tRNA and stalled ribosomes. The presence of a HisRS-like domain in GCN2, normally associated with the ability to bind and aminoacylate tRNAs, led to the hypothesis that eIF2 kinase activity is regulated by the direct binding of this domain to uncharged tRNA. Here we solved the structure of the HisRS-like domain in the context of full-length GCN2 by cryoEM. Structure and function analysis shows the HisRS-like domain of GCN2 has lost tRNA charging, ATP binding, and histidine binding activity but retains the ability to bind tRNA. Hydrogen deuterium exchange mass spectrometry (HX-MS), site-directed mutagenesis and computational docking experiments support a tRNA binding model that overlaps with but is partially shifted from that employed by bona fide HisRS enzymes. These results demonstrate that the HisRS-like domain of GCN2 is a pseudoenzyme and advance our understanding of GCN2 regulation and function.

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Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress.

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Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress

Project description:Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress

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Transcriptional responses to TNF following HFol treatment of wild type and GCN2 depleted synoviocytes

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Ssd1 and Gcn2 suppress global translational efficiency in replicatively aged yeast, while their activation in young cells extends lifespan

Project description:Using ribosome profiling, we find globally reduced translation efficiency during mitotic / replicative aging in budding yeast. Two mechanisms contribute to this: Firstly, the mRNA binding protein Ssd1 is induced during aging, sequestering mRNAs to P-bodies and stress granules that are abundant in old cells. Indeed, overexpression of Ssd1 reduced protein synthesis in young cells and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, the Gcn2 kinase is activated in old cells, phosphorylating and inactivating the translational initiation factor eIF2α. Accordingly, deletion of GCN2 reduced the translational defect of old cells. Furthermore, overexpressing an uncharged tRNA to fully activate Gcn2, or overexpression of its downstream mediator, Gcn4, extended replicative lifespan in a manner that was mostly dependent on autophagy without inhibiting the TOR pathway. As such, Ssd1 induction, activation of the integrated stress response or autophagy are favorable TOR-independent therapeutic targets for lifespan extension.

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