Relocalization of eIF4E by its binding partners upon stress

Translation is the vital process by which the information contained in messenger RNAs (mRNA) is used to synthesise proteins. This is a highly regulated process that involves a complex machinery and tight control at every step. In eukaryotes, translation initiation is the rate-limiting step and the most tightly controlled. The translation of an mRNA is preceded by multiple post-transcription steps including, splicing, export and chemical modification including the addition of a 5'-end cap structure. The initiation factor eIF4E binds to this cap structure while in the nucleus, and initiates the translation by recruiting the ribosome after export to the cytoplasm. Controlling the availability of eIF4E within the various compartments of the cell has a direct effect on the efficiency of translation initiation and indirectly on the rate of proliferation of the cell. On the other hand, disturbing the level of eIF4E synthesis could lead to various pathologies especially tumour development. eIF4E requires multiple binding partners to fulfill its mission. The factor 4E-T is involved in eIF4E transport, while eIF4G enhances the binding of eIF4E to the cap structure. eIF4E can be inactivated upon sequestration by the 4E Binding Protein (4E-BP) who competes with eIF4G for binding of eIF4E.;In our study, we focused on the role of eIF4E as a key player for cellular survival under stressful conditions. Therefore, identifying reagents that induce the relocalization of eIF4E to the nucleus or to SGs could help in the development of anti-proliferative drugs.;The localization of eIF4E inside the cell is clearly critical for its normal function. It is known that many external stresses can influence cellular translation and this prompted us to investigate the effect of such stresses on the cellular localization of eIF4E and to study the role of eIF4E-binding partners under these conditions. The present work demonstrates that, during heat shock and oxidative stress, 4E-BP plays an essential role in controlling the localization of eIF4E to the stress response cytoplasmic foci, known as the stress granules (SGs). In addition, eIF4E is partially retained in the nucleus during heat shock but not in oxidative stress. These observations suggest that upon stress the cellular translation mechanism is delayed or even stopped by reducing the availability of eIF4E to the translation complex. On the other hand, we show that eIF4E nuclear translocation upon poliovirus infection is correlated with eIF4G cleavage. This translocation could favour the shutdown of host cell protein synthesis by reducing the cap dependent translation and preventing mRNA circularization.