Eukaryotic translation initiation factor 6 (eIF6) 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. We here show a novel mode of eIF6 regulation by Glycogen Synthase Kinase-3 (GSK3) that is predominantly active in response to serum starvation. Both GSK3α and GSK3β phosphorylate human eIF6. Multiple residues in the C-terminus of eIF6 are phosphorylated by GSK3 in a sequential manner. In response to serum starvation, eIF6 accumulates in the cytoplasm and this altered localization is dependent on phosphorylation by GSK3. Disruption of eIF6 phosphorylation exacerbates the translation inhibitory response to serum starvation and stalls cell growth. 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.
Gene expression is regulated at multiple levels in eukaryotic cells. Regulation at the post-transcriptional level is modulated by various trans-acting factors that bind to specific sequences in the messenger RNA (mRNA). The binding of different trans factors influences various aspects of the mRNA such as degradation rate, translation efficiency, splicing, localization, etc. MicroRNAs (miRNAs) are short endogenous ncRNAs that combine with the Argonaute to form the microRNA-induced silencing complex (miRISC), which uses base-pair complementation to silence the target transcript. RNA-binding proteins (RBPs) contribute to post-transcriptional control by influencing the mRNA stability and translation upon binding to cis-elements within the mRNA transcript. RBPs have been shown to impact gene expression through influencing the miRISC biogenesis, composition, or miRISC-mRNA target interaction. While there is clear evidence that those interactions between RBPs, miRNAs, miRISC and target mRNAs influence the efficiency of miRISC-mediated gene silencing, the exact mechanism for most of them remains unclear. This review summarizes our current knowledge on gene expression regulation through interactions of miRNAs and RBPs.
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.
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