The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila

Abstract

PERK is an endoplasmic reticulum (ER) transmembrane sensor that phosphorylates eIF2α to initiate the Unfolded Protein Response (UPR). eIF2α 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 <i>Drosophila</i> indicated that delta-family glutathione-S-transferases (<i>gstD</i>) are prominently induced by the UPR-activating transgene <i>Rh1^G69D. Perk</i> was necessary and sufficient for such <i>gstD</i> induction, but <i>ATF4</i> was not required. Instead, <i>Perk</i> and other regulators of eIF2α phosphorylation regulated Xrp1 protein levels to induce <i>gstDs</i>. The <i>Xrp1</i> 5' leader has a conserved upstream Open Reading Frame (uORF) analogous to those that regulate <i>ATF4</i> translation. The <i>gstD-GFP</i> 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.