Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE188460 | GEO | 2022/12/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

The role of GCN2 kinase in amino acid dependent longevity and feeding behaviour in Drosophila

Project description:Dietary amino acids restriction extends lifespan in diverse species ranging from flies to mammals. The evolutionarily conserved serine/threonine kinase General Control Nonderepressible 2 (GCN2) is a key sensor of amino acid deficiency and has been implicated in lifespan regulation upon dietary restriction. However, the role of individual essential amino acids (EAA) in modulating organismal lifespan and the underlying molecular mechanisms through which EAA mediate these effects are only partially understood. We generated a novel Drosophila GCN2 null mutant and systematically analyzed its response to individual amino acid deficiency.

2022-06-03 | GSE203210 | 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 is required to maintain core body temperature in mice during acute cold.

Project description:Non-shivering thermogenesis in the brown adipose tissue (BAT) of rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. Therefore, it is critical to identify signaling pathways which aid in nutrient delivery within this thermogenic tissue.To understand the contribution of the integrated stress response (ISR) in directing adaptive thermogenesis, we examined the role of the kinase activity of general control nonderepressible 2 (GCN2) within the BAT during acute cold exposure. We hypothesized that under hypothermic conditions, GCN2 maintains thermogenesis via ISR gene targets such as fibroblast growth factor 21 (FGF21), that triggers thermogenic uncoupling in BAT. In alignment with our hypothesis, both female and male mice either lacking GCN2 or administered a small molecule inhibitor of GCN2 were profoundly intolerant to acute cold stress. However, while GCN2 deletion in male mice impeded liver-derived FGF21 expression, it did not affect FGF21 levels in females, suggesting an alternative role for GCN2 in the maintenance of thermogenesis. Within the BAT, acute cold exposure increased ISR target genes and thermogenic genes regardless of GCN2 status and sex. RNA sequencing in BAT during cold exposure revealed a gene signature that identified actomyosin mechanics and transmembrane transport as the top two processes requiring GCN2. The top gene signature included cytoskeletal and class II myosin heavy chain genes critical for maximal thermogenesis during cold stress. The second gene signature included amino acid transporters which corresponded with higher circulating amino acids. In conclusion, we identify a novel role for GCN2 activation during acute cold exposure to facilitate mechanosensitive cell signaling and use of amino acids for adaptive thermogenesis.

2023-11-21 | GSE234972 | 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

Roles of activating transcription factor 4 in the murine response to asparaginase in liver.

Project description:In liver, the anti-leukemic agent asparaginase (ASNase) increases phosphorylation of eukaryotic initiation factor 2 by general control nonderepressible 2 (GCN2) kinase. This event promotes gene-specific translation of activating transcription factor 4 (ATF4) which alters gene expression in response to amino acid depletion. The objective of this study was to investigate the role of GCN2 versus ATF4 in controlling the global transcriptome to ASNase in liver. We compared global gene expression patterns in livers from wildtype,Gcn2-/-, andAtf4-/-mice (all on C57BL/6J background) treated with ASNase or phosphate buffered saline (PBS) excipient. These analyses revealed that ATF4 controls a hepatic gene expression profile that partially overlaps with GCN2 both basally and following amino acid depletion by ASNase.

2017-04-30 | GSE92364 | GEO

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.

2024-03-06 | GSE239867 | GEO

Ethylene modulates the dynamics of translation via GCN2 and EIN2 in Arabidopsis under submergence

Project description:General translational repression is predicted as a key process to reduce energy consumption under hypoxia. We have previously showed that mRNA loading onto polysome is reduced in Arabidopsis under submergence. Here, we showed that plant stress activated GCN2 (general control nonderepressible 2) can phosphorylate eIF2a (Eukaryotic Initiation Factor 2a) in Arabidopsis under submergence, and this process is reversible after desubmergence. Compared to the wild-type, the reduction in polysome loading during submergence was less severe in the gcn2 mutant. Transgenic lines overexpressing GCN2 had more ATP and conferred better tolerance under submergence, suggesting that GCN2 might modulate the dynamics of translation to adjust the energy homeostasis under hypoxia. Interestingly, GCN2-eIF2a signaling was activated by ethylene under submergence. However, GCN2 activity was not affected in ein2-5 and eil1ein3 under submergence, suggesting that GCN2 activity was regulated by noncanonical ethylene signaling. In addition, the polysome loading was retained in both ein2-5 and etr1-1 under submergence, implying that ethylene modulated the dynamic translation under submergence via EIN2 and GCN2. Notably, our NGS analysis also demonstrated that EIN2 and GCN2 regulated the translation of 23 core hypoxia genes as well as 53% translational repressed genes under submergence. On the other hand, EIN2 and GCN2 also affected the expression of genes involved in hypoxic response, ethylene response, biotic stress and negative regulation of cytokinin signaling. Taken together, these demonstrated that entrapped ethylene triggers GCN2 and EIN2 to ensure the translation of stress required proteins under submergence and also provide a step stone for future investigation how eukaryotic cells modulate the translation to response for the changeable environments.

2022-06-08 | GSE149414 | GEO

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

2010-08-01 | GSE22452 | GEO

GCN2 Adapts Protein Synthesis to Scavenging-Dependent Growth

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

2022-10-13 | PXD028143 | Pride

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data