Professor of Molecular Virology, Utrecht University, Utrecht, THE NETHERLANDS

Friday 29 November 2019 | 12:00 noon – ICGEB Trieste, ITALY

A novel viral mechanism to prevent translation inhibition and activation of the integrated stress response

Hosts: O. Burrone/G. Papa

Eukaryotic cells, when exposed to environmental or internal stress (e.g. virus infection), activate the integrated stress response (ISR) to restore homeostasis and promote cell survival. Specific stress stimuli prompt dedicated stress kinases to phosphorylate translation initiation factor 2 (eIF2). Phospho-eIF2 (p-eIF2) in turn sequesters the eIF2-specific guanidine exchange factor (GEF) eIF2B to block eIF2 recycling, thereby halting translation initiation and reducing global protein synthesis. To circumvent stress-induced translational shut-down, viruses encode ISR antagonists. Those identified so far prevent or reverse eIF2 phosphorylation. We have identified coronavirus and picornavirus proteins that counteracts the ISR at its very core by acting as a competitive inhibitor of p-eIF2•eIF2B interaction, allowing continued formation of the eIF2-GTP-tRNAiMet ternary complex and unabated global translation at high p-eIF2 levels that would otherwise cause translational arrest.