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.

真核细胞在暴露于环境或内部应力时会激活整合的应激反应（ISR）以恢复体内平衡并促进细胞存活。比应力刺激促使专用的应力激酶磷酸化真核起始因子2（eIF2）。磷酸化的eIF2（p-eIF2）依次隔离eIF2特异性鸟嘌呤交换因子eIF2B，以阻止eIF2循环，从而停止翻译起始并减少整体蛋白质合成。为了规避压力引起的翻译关闭，病毒编码ISR拮抗剂。迄今确定的那些阻止或逆转了eIF2磷酸化。现在，我们描述两种病毒蛋白，一种来自冠状病毒，另一种来自小核糖核酸病毒，它们通过充当p-eIF2-eIF2B相互作用的竞争性抑制剂，独立获得了抵抗ISR核心的能力。这样可以继续形成eIF2-GTP-Met-tRNAi三元复合物，并且在高p-eIF2水平下整体翻译不受影响，否则将导致翻译停滞。我们得出的结论是，eIF2和p-eIF2与eIF2B的相互作用不同，因此可以选择性地抑制p-eIF2-eIF2B的关联。