Fig. 2. Regulation of the PERK/ATF4 pathway in Drosophila. (A) A schematic diagram of the pathway initiated by the eIF2alpha kinases, PERK and GCN2. These kinases are activated by distinct types of stress and phosphorylate eIF2alpha. This results in the overall translation attenuation, but at least two transcripts in Drosophila enhance their translation during such conditions: ATF4 is a transcription factor that induces stress response genes, and PPP1R15 is a phosphatase subunit that helps to de-phosphorylate eIF2alpha as a feedback mechanism. (B) uORFs in the 5’ UTR allow enhanced ATF4 synthesis under conditions of eIF2alpha phosphorylation. ATF4 5’ UTR has multiple uORFs, and only two are shown for simplicity. eIF2alpha helps to charge 40S ribosomes with initiator methionyl tRNA after the synthesis of uORF1. When eIF2alpha is active, 40S ribosomes efficiently recognize uORF2 for translation. uORF2 overlaps with ATF4 ORF, and interferes with ATF4 ORF translation. When eIF2alpha is phosphorylated, 40S ribosome’s ability to recognize the uORF2 is compromised, bypassing its AUG to allow the recognition of the ATF4 ORF.