Translational control in eukaryotes : discovery of a novel human eukaryotic translation initiation factor and its role in the shutoff of host cell protein synthesis following entero- and rhinovirus infections

The eukaryotic initiation factor (eIF) 4F complex is composed of three polypeptides: eIF4A, eIF4E and eIF4G. eIF4E is the cap-binding subunit; eIF4A is the component which exhibits RNA helicase activity and is thought to unwind the secondary structure present at the 5' leader sequences of mRNAs; eIF4G serves as a scaffold to bring together eIF4E, eIF4A, with eIF3, thus recruiting the mRNA to the 40S small ribosomal subunit. Here, I describe the identification and characterization of a novel homologue of eIF4G that we have termed eIF4GII. We renamed the previously discovered polypeptide, eIF4GI. eIF4GI and eIF4GII are 46% identical at the amino acid level. eIF4GII interacts directly with eIF4E, eIF4A, eIF3 and the poly(A) binding protein. eIF4GII restores cap-dependent translation in a reticulocyte lysate which had been pretreated with rhinovirus 2A protease to cleave endogenous eIF4G. Our findings indicate that eIF4GII is a functional homologue of eIF4GI.In contrast to cellular mRNAs, entero- and rhinovirus RNAs do not possess a cap structure, and their translation is mediated by ribosome binding to an internal ribosome entry site present within the 5' untranslated region. The cleavage of eIF4G induced by the viral protease 2A is thought to be responsible for the shutoff of host protein synthesis in entero- and rhinovirus-infected cells. Nonetheless, in virus-infected cells, a lack of correlation between eIF4GI cleavage and inhibition of host translation is observed. eIF4GII, like eIF4GI, is also cleaved upon viral infection. Here, I present data showing that the kinetics of cleavage of eIF4GII perfectly coincide with the inhibition of cellular protein synthesis observed after entero- and rhinovirus infection. Thus, proteolysis of both eIF4GI and eIF4GII appears to be required for the shutoff of host protein synthesis after entero- and rhinovirus infections