It is sometimes difficult to tease apart the molecular functions and biological roles of paralog proteins. In this preprint we do just that for GIGYF1, a protein that has for years been overshadowed by its more prominent paralogue, GIGYF2.
In a previous report, we illuminated the crucial role of the cap-binding protein and translational repressor, 4EHP (eIF4E2), in suppressing Interferon ß production during viral infections. In a subsequent publication, we unveiled how the SARS-CoV-2 virus co-opts this mechanism by targeting the GIGYF2/4EHP complex.
Our new report elucidates the molecular mechanism underlying repression by GIGYF1, which operates independently of 4EHP and relies on GIGYF1's ability to disrupt the recruitment of the eIF3 complex and small ribosomal subunit to the mRNA cap via eIF4G1. Our research underscores the vital role of this mechanism in modulating the host's response to viral infections, at least partly through the repression of translation of the Ifnb1 mRNA upon viral infection. Considering the diverse repertoire of RNA-binding proteins that can recruit GIGYF1, our findings indicate that this mechanism is poised to influence a wide range of cellular mRNAs in a context-dependent manner. Consequently, it is expected to have a profound impact on a diverse array of cellular processes.