De Virgilio, Claudio Dokládal, Ladislav Stumpe, Michael Pillet, Benjamin Hu, Zehan Garcia Osuna, Guillermo Miguel Kressler, Dieter Dengjel, Jörn 2021 The conserved Gcn2 protein kinase mediates cellular adaptations to amino acid limitation through translational control of gene expression that is exclusively executed by phosphorylation of the α-subunit of the eukaryotic translation initiation factor 2 (eIF2α). Using quantitative phosphoproteomics, however, we discovered that Gcn2 targets auxiliary effectors to modulate translation. Accordingly, Gcn2 also phosphorylates the β-subunit of the trimeric eIF2 G protein complex to promote its association with eIF5, which prevents spontaneous nucleotide exchange on eIF2 and thereby restricts the recycling of the initiator methionyl-tRNA-bound eIF2-GDP ternary complex in amino-acid-starved cells. This mechanism contributes to the inhibition of translation initiation in parallel to the sequestration of the nucleotide exchange factor eIF2B by phosphorylated eIF2α. Gcn2 further phosphorylates Gcn20 to antagonize, in an inhibitory feedback loop, the formation of the Gcn2-stimulatory Gcn1-Gcn20 complex. Thus, Gcn2 plays a substantially more intricate role in controlling translation initiation than hitherto appreciated. application/pdf https://folia.unifr.ch/global/documents/319831 https://folia.unifr.ch/documents/319831/files/molecular-cell-d-20-01963_r5copy_1.pdf https://folia.unifr.ch/documents/319831/files/Global_phosphoproteomics_Supplemental_information.pdf https://folia.unifr.ch/documents/319831/files/mmc2.xlsx https://folia.unifr.ch/documents/319831/files/Table S2.xlsx eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molcel.2021.02.037 info:eu-repo/semantics/altIdentifier/pmid/33743194 info:eu-repo/semantics/openAccess License undefined Mol Cell. - 2021, vol. 81, no. 6, p. 1879-1889 TORC1 Gcn2 Gcn20 amino acid starvation eIF2 eIF5 eukaryotic initiation factor 2 eukaryotic initiation factor 5 general control nonderepressible 2 target of rapamycin complex 1 translation initiation info:eu-repo/classification/udc/57 Global phosphoproteomics pinpoints uncharted Gcn2-mediated mechanisms of translational control http://purl.org/coar/resource_type/c_6501