Regulation of eIF6 through multisite and sequential phosphorylation by GSK3β

Abstract

Eukaryotic translation initiation factor 6 is essential for the synthesis of 60S ribosomal subunits and for regulating the association of 60S and 40S ribosomal subunits. A mechanistic understanding of how eIF6 modulates protein synthesis in response to stress, specifically starvation-induced stress, is lacking. Our studies have uncovered a novel mode of eIF6 regulation by Glycogen Synthase Kinase-3 that is predominantly active in response to serum starvation. Human eIF6 is phosphorylated by GSK3 at a multisite motif in the C-terminal tail.Robust and sequential phosphorylation by GSK3 requires phosphorylation at a priming site. In response to serum starvation, eIF6 accumulates in the cytoplasm and this altered subcellular localization is dependent on GSK3 activity. Cells expressing the phosphodead mutant exhibit increased levels of free 60S subunits and display a further inhibition translation in response to serum starvation, which deregulates the cellular response to starvation. These results suggest that eIF6 regulation by GSK3 contributes to the attenuation of global protein synthesis that is critical for adaptation to starvation-induced stress.