eIF4E‐homologous protein (4EHP): a multifarious cap‐binding protein

Abstract

The cap-binding protein 4EHP/eIF4E2 has been a recent object of interest in the field of post-transcriptional gene regulation and translational control. From ribosome-associated quality control, to RNA decay and microRNA-mediated gene silencing, this member of the eIF4E protein family regulates gene expression through numerous pathways. Low in abundance but ubiquitously expressed, 4EHP interacts with different binding partners to form multiple protein complexes that regulate translation in a variety of biological contexts. Documented functions of 4EHP primarily relate to its role as a translational repressor, but recent findings indicate that it might also participate in the activation of translation in specific settings. In this review, we discuss the known functions, properties and mechanisms that involve 4EHP in the control of gene expression. We also discuss our current understanding of how 4EHP processes are regulated in eukaryotic cells, and the diseases implicated with dysregulation of 4EHPmediated translational control.

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

“…8a). To investigate the helical organization of GIGYF2 (744-940), we mapped this region back to a full-length threedimensional model of human GIGYF2 as predicted by AlphaFold 2 16,41 . GIGYF2 (744-940) corresponds to a region in the model that is confidently predicted (Extended Data Fig.…”

“…Consequently, 4EHP represses mRNAs translation upon recruitment to target mRNAs (e.g. via 4E-T protein upon recruitment by microRNAs) [16][17][18][19] . GIGYF2 [Grb10-interacting GYF (glycine, tyrosine, phenylalanine) protein 2] is another protein among others that is recruited by 4EHP to the mRNA to inhibit translation or decrease stability [20][21][22][23][24][25] .…”

The SARS-CoV-2 protein NSP2 impairs the silencing capacity of the human 4EHP-GIGYF2 complex

“…The role of 4EHP-GIGYF2 as a translational repressor has been described in various contexts (for review, see (Christie and Igreja, 2021)). Having shown that NSP2 directly targets the 4EHP-GIGYF2 complex through at least two contact points, namely the region 743-1,085 of GIGYF2 and 4EHP itself, we wished to assess whether the silencing capacity of 4EHP-GIGYF2 could be altered by NSP2.…”

“…The cap-binding eIF4E-Homologous Protein (4EHP) is an integral component of post-transcriptional silencing mechanisms through competing with the eIF4F complex for binding to the mRNA 5 0 cap (Christie and Igreja, 2021). In complex with the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) protein 2 (GIGYF2), the cap-binding activity of 4EHP is required for the optimal translational repression by mi-croRNAs (miRNAs), as well as the RNA-binding proteins ZNF598 and tristetraprolin (TTP) (Morita et al, 2012;Fu et al, 2016;Villaescusa et al, 2009;Cho et al, 2005Cho et al, , 2006Chapat et al, 2017b;Chen and Gao, 2017).…”

Drosophila cap-binding protein eiF4EHP promotes translation via a 3’UTR-dependent mechanism under hypoxia and contributes to fruit fly adaptation to oxygen variations

“…The Drosophila eiF4E1-related protein eiF4EHP and its mammalian homolog eiF4E2 were primarily described as translational repressors of several mRNAs. However, eiF4E2 has also been reported to specifically activate mRNA translation in different cellular contexts including hypoxia (reviewed in 21 ). Interestingly, hypoxic treatment induces an increase of eIF4EHP detected in both head (Fig.…”