Inhibition of the integrated stress response by viral proteins that block p-eIF2-eIF2B association

Eukaryotic cells, when exposed to environmental or internal stress, activate the integrated stress response (ISR) to restore homeostasis and promote cell survival. Specific stress stimuli prompt dedicated stress kinases to phosphorylate eukaryotic initiation factor 2 (eIF2). Phosphorylated eIF2 (p-eIF2) in turn sequesters the eIF2-specific guanine exchange factor eIF2B to block eIF2 recycling, thereby halting translation initiation and reducing global protein synthesis. To circumvent stress-induced translational shutdown, viruses encode ISR antagonists. Those identified so far prevent or reverse eIF2 phosphorylation. We now describe two viral proteins-one from a coronavirus and the other from a picornavirus-that have independently acquired the ability to counteract the ISR at its very core by acting as a competitive inhibitor of p-eIF2-eIF2B interaction. This allows continued formation of the eIF2-GTP-Met-tRNAi ternary complex and unabated global translation at high p-eIF2 levels that would otherwise cause translational arrest. We conclude that eIF2 and p-eIF2 differ in their interaction with eIF2B to such effect that p-eIF2-eIF2B association can be selectively inhibited. The AcP10 protein-an active uridine kinase, encoded by the beluga whale coronavirus SW1-is an antagonist of the integrated stress response that acts downstream of phosphorylation of the translation initiation factor eIF2, irrespective of which eIF2 kinase is activated. AcP10 acts as a competitive inhibitor of the eIF2[P]-eIF2B interaction by binding to eIF2B. A protein with a similar function is also encoded by Aichivirus, a picornavirus.