Shielding the mRNA-translation factor eIF2B from inhibitory p-eIF2 as a viral strategy to evade protein kinase R-mediated innate immunity

The interferon-regulated kinase PKR (protein kinase RNA-activated) is a potent innate immune factor against a broad range of viruses. Being part of the integrated stress response (ISR), its restrictive effect is predominantly exerted by phosphorylating the eukaryotic translation-initiation factor eIF2, thereby turning it into an inhibitor of translation-initiation factor eIF2B. A plethora of viruses are known to evade the shutdown of cellular mRNA translation by interfering either with PKR activation or with eIF2 phosphorylation. Recently, a novel PKR evasion strategy was described: proteins from three taxonomically distinct RNA viruses allow for full PKR activation and eIF2 phosphorylation in the infected cell, but protect eIF2B from inhibition by phosphorylated eIF2, thus enabling mRNA translation in the presence of an activated ISR.