%0 Journal Article %A Courtney F. Jungers %A Jonah M. Elliff %A Daniela S. Masson-Meyers %A Christopher J. Phiel %A Sofia Origanti %T Regulation of eIF6 through multisite and sequential phosphorylation by GSK3β %D 2019 %R 10.1101/476978 %J bioRxiv %P 476978 %X Eukaryotic translation initiation factor 6 is essential for the synthesis of 60S ribosomal subunits and for regulating the association of 60S and 40S subunits. A mechanistic understanding of how eIF6 modulates translation in response to stress, specifically starvation-induced stress, is lacking. Our studies have uncovered a novel mode of eIF6 regulation by GSK3 that is predominantly active in response to serum starvation. Human eIF6 is phosphorylated by GSK3β at a multisite motif in the C-terminus. Sequential phosphorylation by GSK3β requires phosphorylation at a priming site. In response to serum starvation, eIF6 accumulates in the cytoplasm and this altered localization is dependent on GSK3. Disruption of eIF6 phosphorylation enhances translation inhibition and markedly sensitizes the cells to serum starvation. These results suggest that eIF6 regulation by GSK3β contributes to the attenuation of global protein synthesis that is critical for adaptation to starvation-induced stress. %U https://www.biorxiv.org/content/biorxiv/early/2019/06/20/476978.full.pdf