Activation of Gcn2 in response to different stresses

Anda, Silje; Zach, Róbert; Grallert, Beáta

doi:10.1371/journal.pone.0182143

Cited by 68 publications

(75 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Under optimal growth conditions, eIF2 properly initiates translation. However, upon amino acid starvation or exposure to different stress conditions, the Gcn2 kinase is activated and phosphorylates eIF2α, which interferes with 5′cap-dependent mRNA translation 19,[28][29][30] . Consistent with this, we observed that the expression of the GCN4-lacZ reporter construct was not up-regulated by amino acid starvation (3-AT treatment) or upon iron depletion in a gcn2Δ mutant ( Fig.…”

Section: The Translational State Of Specific Transcripts Is Differentmentioning

confidence: 99%

“…under amino acid starvation conditions occurs through the binding of uncharged tRNAs to its histidyl-tRNA synthetase (HisRS)-like domain, a process that requires the Gcn1-Gcn20 protein complex 25,30 . To investigate whether the activation of Gcn2 kinase in response to iron deficiency was mediated by this mechanism, we analyzed the polysome profile of wild-type and gcn1∆ cells under iron-deficient conditions.…”

Section: The Repression Of Translation Under Iron Deficiency Dependsmentioning

confidence: 99%

See 1 more Smart Citation

Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2α pathway

Romero

Ramos-Alonso

Alepuz

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Iron is an essential element for all eukaryotic organisms because it participates as a redox active cofactor in a wide range of biological processes, including protein synthesis. Translation is probably the most energy consuming process in cells. Therefore, one of the initial responses of eukaryotic cells to stress or nutrient limitation is the arrest of mRNA translation. In first instance, the budding yeast Saccharomyces cerevisiae responds to iron deficiency by activating iron acquisition and remodeling cellular metabolism in order to prioritize essential over non-essential iron-dependent processes. We have determined that, despite a global decrease in transcription, mRNA translation is actively maintained during a short-term exposure to iron scarcity. However, a more severe iron deficiency condition induces a global repression of translation. Our results indicate that the Gcn2-eIF2α pathway limits general translation at its initiation step during iron deficiency. This bulk translational inhibition depends on the uncharged tRNA sensing Gcn1-Gcn20 complex. The involvement of the Gcn2-eIF2α pathway in the response to iron deficiency highlights its central role in the eukaryotic response to stress or nutritional deprivation, which is conserved from yeast to mammals.

show abstract

Section: The Translational State Of Specific Transcripts Is Differentmentioning

confidence: 99%

Section: The Repression Of Translation Under Iron Deficiency Dependsmentioning

confidence: 99%

Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2α pathway

Romero

Ramos-Alonso

Alepuz

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Given the speed at which GCN2 is activated, the most likely candidates are a direct biochemical activation of the kinase by a redox-active compound or by an intermediate that is released from the chloroplast during ROS stress. This very question also remains unresolved in every other organism, fission yeast, budding yeast, mammals, where ROS-activation of eIF2a kinases has been observed over the past 15 years (Shenton et al, 2006;Anda et al, 2017) and remains to be explored in more detail.…”

Section: Gcn2 Activation By Light and Rosmentioning

confidence: 99%

Light activates the translational regulatory GCN2 kinase via reactive oxygen species emanating from the chloroplast

Lokdarshi

Guan

Camacho

et al. 2019

Preprint

View full text Add to dashboard Cite

Word count (main text excluding legends, references): 7,751, 12 figures. ABSTRACTCytosolic mRNA translation is subject to global and mRNA-specific controls. Phosphorylation of translation initiation factor eIF2a anchors a reversible switch that represses translation globally.The stress-responsive GCN2 kinase is the only known kinase for eIF2a in Arabidopsis. Here we show that conditions that generate reactive oxygen species (ROS) in the chloroplast, such as darklight transitions, high light, and the herbicide methyl viologen all rapidly activated the GCN2 kinase, whereas mitochondrial and ER stress did not. In addition, GCN2 activation was light dependent and mitigated by photosynthesis inhibitors and ROS quenchers. Accordingly, seedling growth of multiple gcn2 mutant alleles was retarded under conditions of excess light, implicating the GCN2-eIF2a pathway in responses to light and associated ROS. Once activated, the GCN2 kinase preferentially suppressed the ribosome loading of mRNAs for functions such as mitochondrial ATP synthesis, the chloroplast thylakoids, vesicle trafficking, and translation. The transcriptome of gcn2 mutants was sensitized to abiotic stress, including oxidative stress, as well as innate immune responses. Accordingly, gcn2 displayed defects in immune priming by the fungal elicitor, chitin. In conclusion, we provide evidence that reactive oxygen species produced by the photosynthetic apparatus help to activate the highly conserved GCN2 kinase, leading to eIF2a phosphorylation and thus affecting the status of the cytosolic protein synthesis apparatus.

show abstract

“…In S. cerevisiae, divergent stresses other than AAS such as glucose deprivation and high salt activates Gcn4 in Gcn2-tRNA binding motif dependent manner indicating the accumulation of uncharged tRNA as the responsible mechanism [1]. Also in Schizosaccharomyces pombe (S. Pombe), uncharged tRNA binding to Gcn2 is essential for the response to AAS as well as to hydrogen peroxide (H 2 O 2 ) and UV radiation, and these responses require Gcn1 [9]. Recent analysis also showed that GCN2 mediates ISR activation by the unfolded protein response in PLOS GENETICS mitochondria (UPR mt ) in Caenorhabditis elegans (C. elegans) [10] and that its activation leads to longevity expansion in both C. elegans and Drosophila [10,11].…”

Section: Introductionmentioning

confidence: 99%

Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice

et al. 2020

View full text Add to dashboard Cite

Amino acids exert many biological functions, serving as allosteric regulators and neurotransmitters, as constituents in proteins and as nutrients. GCN2-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) restores homeostasis in response to amino acid starvation (AAS) through the inhibition of the general translation and upregulation of amino acid biosynthetic enzymes and transporters by activating the translation of Gcn4 and ATF4 in yeast and mammals, respectively. GCN1 is a GCN2-binding protein that possesses an RWD binding domain (RWDBD) in its C-terminus. In yeast, Gcn1 is essential for Gcn2 activation by AAS; however, the roles of GCN1 in mammals need to be established. Here, we revealed a novel role of GCN1 that does not depend on AAS by generating two Gcn1 mutant mouse lines: Gcn1-knockout mice (Gcn1 KO mice (Gcn1-/-)) and RWDBD-deleted mutant mice (Gcn1 ΔRWDBD mice). Both mutant mice showed growth retardation, which was not observed in the Gcn2 KO mice, such that the Gcn1 KO mice died at the intermediate stage of embryonic development because of severe growth retardation, while the Gcn1 ΔRWDBD embryos showed mild growth retardation and died soon after birth, most likely due to respiratory failure. Extension of pregnancy by 24 h through the administration of progesterone to the pregnant mothers rescued the expression of differentiation markers in the lungs and prevented lethality of the Gcn1 ΔRWDBD pups, indicating that perinatal lethality of the Gcn1 ΔRWDBD embryos was due to simple growth retardation. Similar to the yeast Gcn2/ Gcn1 system, AAS-or UV irradiation-induced elF2α phosphorylation was diminished in the Gcn1 ΔRWDBD mouse embryonic fibroblasts (MEFs), suggesting that GCN1 RWDBD is responsible for GCN2 activity. In addition, we found reduced cell proliferation and G2/M arrest accompanying a decrease in Cdk1 and Cyclin B1 in the Gcn1 ΔRWDBD MEFs. Our

show abstract

Activation of Gcn2 in response to different stresses

Cited by 68 publications

References 46 publications

Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2α pathway

Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2α pathway

Light activates the translational regulatory GCN2 kinase via reactive oxygen species emanating from the chloroplast

Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice

Contact Info

Product

Resources

About