Abstract
mRNA translation is mainly regulated at the level of initiation, a process that involves the synergistic action of the 5' cap structure and the 3' poly(A) tail at the ends of eukaryotic mRNA. The eukaryote initiation factor 4G(eIF4G) is a pivotal scaffold protein that forms a critical link between mRNA cap structure, poly(A) tail, and the small ribosomal subunit. There are two functional homologs of eIF4G in mammals, the original eIF4G, renamed eIF4GI, and eIF4GII that functionally complements eIF4GI. To date, biochemical and functional analysis have not identified differential activities for eIF4GI and eIF4GII. In this report, we demonstrate that eIF4GII, but not eIF4GI, is selectively recruited to capped mRNA at the onset of cell differentiation. This recruitment is coincident with a strong and long-lasting phosphorylation of eIF4E and the release of 4E-BP1, a suppressor of eIF4E function, from the cap structure, without a concomitant change in 4E-BP1's phosphorylation. Our data further indicate that cytokines such as thrombopoietin can differentially regulate eIF4GI/II activities. These results provide the first evidence that eIF4GI/II does fulfill selective roles in mammalian cells.
Highlights
Cell fate specification is achieved by differential gene expression, which can involve regulation at various levels, including transcription, RNA processing, translation, and posttranslation protein modifications
We demonstrate that eIF4GII, but not eIF4GI, is selectively recruited to capped mRNA at the onset of cell differentiation
The poly(A) tail is recognized by the poly(A)-binding protein (PABP) while the cap structure (m7GpppN) interacts with a protein complex termed the eukaryotic initiation factor 4F(eIF4F), which consists of three subunits: eIF4E, eIF4G, and eIF4A
Summary
Cell fate specification is achieved by differential gene expression, which can involve regulation at various levels, including transcription, RNA processing, translation, and posttranslation protein modifications. EIF4G functions as a pivotal scaffolding factor: in addition to eIF4E and eIF4A, it binds to eIF3, a multiprotein complex directly associated with the small ribosomal subunit, and to PABP, allowing a circularization of the mRNA molecule [46] which explains the synergistic effect of the 5Ј cap and the 3Ј-poly(A) tails of mRNA on translation initiation [15, 35]. Two kinases phosphorylate Ser209 and are targets of the mitogenactivated extracellular-signal-regulated kinases (Erks) and the stress- and cytokine-activated p38 mitogen-activated protein (MAP) kinase pathways These enzymes (Mnk and Mnk2) associate with eIF4G in vivo; this mode of recruitment is thought to ensure that eIF4E is phosphorylated only as a part of the eIF4F complex [41, 50]. The key issue of the effect of phosphorylation on the function of eIF4E or eIF4F remains largely unknown
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