Journal
PLOS GENETICS
Volume 16, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1008693
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Funding
- Japan Society for the Promotion of Science (JSPS) [KAKENHI 26111010, 25293064, 26860178, 17K08616]
- Naito Foundation
- Karoji Memorial Fund for Medical Research
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Author summary The stress response at the translational level is an energetically cost-saving mechanism because translation consumes a considerable amount of energy. Upon exposure to stresses such as that from amino acid starvation (AAS), the translational initiation factor eIF2 alpha is phosphorylated, which represses general translation to save energy. At the same time, eIF2 alpha phosphorylation increases the selective translation of cytoprotective proteins, such as ATF4, that transcriptionally activate the stress response, promoting cell survival. Among four eIF2 alpha kinases, GCN2 responds to AAS and phosphorylates eIF2 alpha. In yeast, Gcn1 is required for Gcn2 activation by AAS, but the roles of GCN1 in mammals remain to be established. Here, we show that GCN1 is involved in GCN2-mediated eIF2 alpha phosphorylation after AAS and UV radiation by generating Gcn1 mutant mice. Interestingly, GCN1 not only regulates the eIF2 alpha-mediated stress response but also the cell cycle and cell proliferation in a GCN2-independent manner. Taking these findings together, we propose that GCN1 integrates cellular information and coordinates the cellular stress response to enhance viability. 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 (elF2 alpha) 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(Delta RWDBD) 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(Delta RWDBD) 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(Delta RWDBD) pups, indicating that perinatal lethality of the Gcn1(Delta RWDBD) embryos was due to simple growth retardation. Similar to the yeast Gcn2/Gcn1 system, AAS- or UV irradiation-induced elF2 alpha phosphorylation was diminished in the Gcn1(Delta RWDBD) 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(Delta RWDBD) MEFs. Our results demonstrated, for the first time, that GCN1 is essential for both GCN2-dependent stress response and GCN2-independent cell cycle regulation.
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