Specific mechanisms of translation initiation in higher eukaryotes: the eIF4G2 story

Abstract

The eukaryotic initiation factor 4G2 (eIF4G2, DAP5, Nat1, p97) was discovered in 1997. Over the past two decades, dozens of papers have presented contradictory data on eIF4G2 function. Since its identification, eIF4G2 has been assumed to participate in noncanonical translation initiation mechanisms, but recent results indicate that it can be involved in scanning as well. In particular, eIF4G2 provides leaky scanning through some upstream open reading frames (uORFs), which are typical for long 5’ UTRs of mRNAs from higher eukaryotes. It is likely the protein can also help the ribosome overcome other impediments during scanning of the 5’ UTRs of animal mRNAs. This may explain the need for eIF4G2 in higher eukaryotes, as many mRNAs that encode regulatory proteins have rather long and highly structured 5’ UTRs. Additionally, they often bind to various proteins, which also hamper the movement of scanning ribosomes. This review discusses the suggested mechanisms of eIF4G2 action, denotes obscure or inconsistent results, and proposes ways to uncover other fundamental mechanisms in which this important protein factor may be involved in higher eukaryotes.

Translational regulation by uORFs and start codon selection stringency

“…In addition to eIF1 and eIF5, the factors eIF3 and eIF4G2 (DAP5) have been linked to start codon selection and uORF regulation. The studies on eIF4G2 have been recently reviewed ( Shestakova et al 2023 ), and it is unclear whether the impact of eIF3 and eIF4G2 on start codon selection is direct or indirect ( She et al 2023 ). Notably, lowered stringency was observed upon knockdown of ribosomal proteins, eIF3 subunits, or eIF4G2 and was correlated with the impact of the knockdowns on cell growth ( She et al 2023 ).…”

Construction and analysis of competitive endogenous RNA networks and prognostic models associated with ovarian cancer based on the exoRBase database

“…EIF4G2 proteins are also known as DAP5, Nat1 and p97. Currently, findings by Shestakova ED et al suggest that EIF4G2 is a helper protein that facilitates elusive translation mechanisms under rare conditions, andits specific role under normal conditions remained unclear until recently [ 30 ]. The study conducted by Liu et al demonstrated that EIF4G2 is upregulated in gastric cancer (GC).…”

mRNA cap-binding protein eIF4E1 is a novel regulator ofToxoplasma gondiilatency

“…Third, a reduction in cap-dependent translation may increase the prevalence of cap-independent translation mechanisms which may play a role in bradyzoite formation. We note that Toxoplasma eIF4G3 lacks an identifiable eIF4E-binding motif and resembles the organization of mammalian eIF4G2/DAP5, which promotes cap-independent translation (20). The finding that BFD2/ROCY1 protein binds the 5’-leader of the bradyzoite-driving transcription factor BFD1 mRNA and is required for the latter’s translational activation (10-12), may indicate that features located within the long 5’-leaders of critical mRNAs are central to promoting bradyzoite formation.…”

“…In contrast, eIF4G3 resembles an N-terminally truncated eIF4G paralog, which is present in some organisms and is missing the eIF4E-interacting motif (Fig. 2B) (20). To further validate the putative interactions between eIF4E1 and eIF4G paralogs, we MYC-tagged each eIF4G paralog at its C-terminus in parasites expressing eIF4E1 HA (Fig.…”