The Transcription Factor Xrp1 is Required for PERK- Mediated Antioxidant Gene Induction in Drosophila

SUMMARY PERK is an endoplasmic reticulum (ER) transmembrane sensor that phosphorylates eIF2 α to initiate the Unfolded Protein Response (UPR). eIF2 α phosphorylation promotes stress-responsive gene expression most notably through the transcription factor ATF4 that contains a regulatory 5’ leader. Possible PERK effectors other than ATF4 remain poorly understood. Here, we report that the bZIP transcription factor Xrp1 is required for ATF4-independent PERK signaling. Cell type-specific gene expression profiling in Drosophila indicated that delta-family glutathione-S-transferases ( gstD ) are prominently induced by the UPR-activating transgene Rh1 G69D . Perk was necessary and sufficient for such gstD induction, but ATF4 was not required. Instead, Perk and other regulators of eIF2 α phosphorylation regulated Xrp1 protein levels to induce gstDs . The Xrp1 5’ leader has a conserved upstream Open Reading Frame (uORF) analogous to those that regulate ATF4 translation. The gstD-GFP reporter induction required putative Xrp1 binding sites. These results indicate that antioxidant genes are highly induced by a previously unrecognized UPR signaling axis consisting of PERK and Xrp1.