Dynamic Interaction of Eukaryotic Initiation Factor 4G1 (eIF4G1) with eIF4E and eIF1 Underlies Scanning-Dependent and -Independent Translation

Abstract

Translation initiation of most mRNAs involves mG-cap binding, ribosomal scanning and AUG selection. Initiation from a mG-cap-proximal AUG can be bypassed resulting in leaky-scanning, except for mRNAs bearing the ranslationnitiator of hort 5'UTR (TISU) element. mG-cap-binding is mediated by eIF4E-eIF4G1 complex. eIF4G1 also associates with eIF1 and both promote scanning and AUG selection. Understanding the dynamics and significance of these interactions is lacking. We report that eIF4G1 exists in two complexes, either with eIF4E or with eIF1. Using an eIF1 mutant impaired in eIF4G1 binding, we demonstrate that eIF1-eIF4G1 interaction is important for leaky scanning and for avoiding mG-cap-proximal initiation. Intriguingly, eIF4E-eIF4G1 antagonizes the scanning promoted by eIF1-eIF4G1 and is required for TISU. Mapping eIF1-binding site on eIF4G1 we unexpectedly found that eIF4E also binds it indirectly. These findings uncover the RNA features underlying regulation by eIF4E-eIF4G1 and eIF1-eIF4G1 and suggest that 43S ribosome transition from the mG-cap to scanning involves relocation of eIF4G1 from eIF4E to eIF1.

Messenger RNAs with large numbers of upstream open reading frames are translated via leaky scanning and reinitiation in the asexual stages of Plasmodium falciparum

“…High concentrations of eIF1 lead to the stringent selection of AUGs having strong Kozak sequences (Loughran et al ., 2012; Andreev et al ., 2015; Fijalkowska et al ., 2017) and the phosphorylation state of eIF1 under stress conditions also determines the selection of the start codon, helping to bypass start codons with weak Kozak sequences (Zach et al ., 2014). Another factor, the m7G-cap-binding factor eIF4G1, also enhances leaky scanning of uORFs near the cap when bound to eIF1 in mammalian cells (Haimov et al ., 2018). Yet another factor that affects leaky scanning in eukaryotes is eIF2 α .…”

So close, no matter how far: multiple paths connecting transcription to mRNA translation in eukaryotes

“…The latter study found that unlike bulk mRNAs, TISU-containing transcripts are resistant to AMPK-mediated translational inhibition, suggesting a direct link between TISU-mediated translation initiation and energy metabolism. While additional studies revealed differential translation initiation factor requirements for TISU-mediated translation (Haimov et al, 2017(Haimov et al, , 2018, establishing it as a noncanonical mode of translation initiation, the mechanism enabling translation upon energy stress is not entirely understood. Indeed, this feature is in contrast to the particularly strong translational arrest of TISU-containing mRNAs upon eIF4E inhibition (Elfakess et al, 2011;Giess et al, 2020).…”

Control of Translation at the Initiation Phase During Glucose Starvation in Yeast

“…With very few exceptions, a new round of translation on mRNA is initiated by the ribosomal small subunit (SSU), which together with specialized initiation factors (IFs) locates the start codon of an open reading frame (ORF) within an mRNA [8,71,78,79,80]. Initiation completes by joining the ribosomal large subunit (LSU) with the SSU to form an elongation-capable complete ribosome [71,80,81,82,83]. Peptide bonds are generally formed as specified by the codon sequence during elongation, which is perhaps the most conserved phase of translation.…”