eIF4E orchestrates mRNA processing, RNA export and translation to modify specific protein production

Abstract

The eukaryotic translation initiation factor eIF4E acts as a multifunctional factor that simultaneously influences mRNA processing, export, and translation in many organisms. Its multifactorial effects are derived from its capacity to bind to the methyl-7-guanosine cap on the 5'end of mRNAs and thus can act as a cap chaperone for transcripts in the nucleus and cytoplasm. In this review, we describe the multifactorial roles of eIF4E in major mRNA-processing events including capping, splicing, cleavage and polyadenylation, nuclear export and translation. We discuss the evidence that eIF4E acts at two levels to generate widescale changes to processing, export and ultimately the protein produced. First, eIF4E alters the production of components of the mRNA processing machinery, supporting a widescale reprogramming of multiple mRNA processing events. In this way, eIF4E can modulate mRNA processing without physically interacting with target transcripts. Second, eIF4E also physically interacts with both capped mRNAs and components of the RNA processing or translation machineries. Further, specific mRNAs are sensitive to eIF4E only in particular mRNA processing events. This selectivity is governed by the presence of cis-acting elements within mRNAs known as USER codes that recruit relevant co-factors engaging the appropriate machinery. In all, we describe the molecular bases for eIF4E's multifactorial function and relevant regulatory pathways, discuss the basis for selectivity, present a compendium of ~80 eIF4E-interacting factors which play roles in these activities and provide an overview of the relevance of its functions to its oncogenic potential. Finally, we summarize early-stage clinical studies targeting eIF4E in cancer.

Keywords: Cap binding protein; capping; eIF4E; gene expression; m7G cap; mRNA export; mRNA maturation; mRNA processing; splicing; translation.

Figure 1.

A, Single section of confocal imaging of U2OS cells stained for eIF4E (sc-271480 anti-eIF4E antibody, red) and DAPI (blue, nuclear dye) showing nuclear and cytoplasmic localization. Left panel shows the overlap between DAPI and eIF4E staining. The right panel shows eIF4E signal alone. B, Confocal imaging of eIF4E in the nucleus of HeLa cells with the antibody 10C6 from [101]. Reprint with permission from Dostie J, Lejbkowicz F, Sonenberg N. Nuclear eukaryotic initiation factor 4E (eIF4E) colocalizes with splicing factors in speckles [99]. White bar = 10μm.

Figure 3.

eIF4E can directly influence RNA fate or indirectly through its capacity to terraform the RNA processing landscape. On the left, interactions between eIF4E target mRNAs and the noted machineries are shown. On the right, numbers of mRNAs in a given process were identified in nuclear, endogenous eIF4E RIP-Seq [54] GSE63265_LY1_4EIP_allreps_counts.Txt.gz and/or RNA-seq splicing data segregated on high and normal-eIF4E AML specimens [100] (https://leucegene.ca/). These strongly suggest that eIF4E can influence a broad array of factors responsible for RNA processing thereby terraforming the RNA processing landscape. Functional categories were assigned using Metascape (metascape.Org).

Figure 2.

The human eIF4E structure binding the m⁷G cap (in red) and known interactions: eIF4E structure and relative position of regions utilized by known partner proteins. The red arrow indicates the cap-binding site with the associated tryptophans in light blue, the purple arrow indicates the positively charge patch, where Importin 8, VPg and EG5 bind with the 2 lysines and the arginine shown. The dorsal surface is also shown and as is the surface used by the NC (non- canonical domain) of eIF4G and 4EBPs with gold yellow arrows (Adapted from [52], PDB3AM7).