The role of eukaryotic translation initiation factor 4E (eIF4E) regulation during viral infection

Translation of mRNA into protein is a fundamental process and requires tight regulation. Primary control occurs at the initiation step. A critical protein for this regulation is the eukaryotic translation initiation factor 4E (eIF4E), which binds to the 5´ cap structure found on all nuclear transcribed mRNAs. This interaction initiates translation by assembling the eIF4F complex on the mRNA, which subsequently recruits the ribosome. The function of eIF4E is regulated in two ways, by the 4E binding proteins (4E-BPs), which disrupt the eIF4F complex and secondly by eIF4E phosphorylation on serine 209. However, the consequences of eIF4E phosphorylation are not clearly understood.;Viral invasion is immediately recognized by the cell and accordingly, several defense mechanisms are activated. One of them entails secretion of type I interferon. This thesis shows that phosphorylation of eIF4E on serine 209 impedes type I interferon production. Cells carrying an altered eIF4E phosphorylation site, impairing eIF4E phosphorylation, secreted elevated levels of type I interferon upon stimulation with synthetic RNA. Consequently, these cells were more protected against infection with interferon sensitive viruses.;In conclusion, regulation of eIF4E is important for picornavirus infection and plays a key role in generating a potent antiviral response.;Cells continuously encounter pathogens including viruses. Lacking their own metabolic machinery, viruses rely on the translational apparatus of the host to produce their proteins. During many viral infections reprogramming of the cellular translation system occurs, favoring translation of viral mRNAs. Altering the eIF4F complex is one means by which reprogramming occurs. Picornaviruses initiate translation of their mRNAs independent of eIF4E through an internal ribosomal entry site (IRES). Work in this thesis demonstrates that eIF4E still impacts picornavirus mRNA translation, but only when viral mRNAs compete with cellular RNAs. IRES mediated translation was strongly enhanced when eIF4E abundance was decreased in an in vitro system by addition of 4E-BP or in vivo by siRNA knock down. Decreased eIF4E abundance reduced cap-dependent translation, but stimulated IRES mediated translation.