We next investigated the importance of ATF4 for GADD34 transcription by monitoring the levels of GADD34 mRNA in ATF4-deficient cells. ATF4 2/2 MEFs displayed higher basal levels of GADD34 mRNA than WT cells. However, in absence of ATF4, MEFs were unable to efficiently induce GADD34 mRNA transcription in response to any of the stimuli tested (Fig. S3 ). GADD34 mRNA expression was induced only 2 fold in ATF4 2/2 MEFs exposed to poly I:C, suggesting that its transcription is mostly dependent on ATF4 in this context. We further investigated P-eIF2a requirement for GADD34 expression and found that eIF2a A/A expressing MEFs were incapable of up-regulating GADD34 in response to poly I:C (Fig. 2C ). Phosphorylation of eIF2a by PKR in response to cytosolic poly I:C induces therefore a specific integrated stress response (ISR), that allows ATF4 translation, its nuclear translocation and subsequent GADD34 mRNA transcription.