The integrated stress response (ISR) results from phosphorylation of the translation initiation factor eIF2, which captures and inhibits the limiting factor eIF2B, thereby slowing translation initiation.[1][2][4] Termination of this reaction requires release of eIF2B from inhibition by phosphorylated eIF2 (P-eIF2).[2][4] The eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bind to the P-eIF2 complex with eIF2B.[2][4] Biochemical studies led by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B showed that R15B allows dephosphorylation of otherwise incompetent P-eIF2 directly on eIF2B.[2][4][6] Thereby, R15B rescues eIF2B from P-eIF2 inhibition, thus protecting translation and cell viability.[1][2][4] The structures revealed that eIF2 and P-eIF2 bind to two different sites on eIF2B, defining a catalytic and inhibitory complex.[1] Phosphorylation of eIF2 is crucial for cell vitality and a target for therapies in diseases such as cancer and neurodegeneration.[1]