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

• Published in: eLife 2021-10, Vol.10
• Main Authors: Brown, Brian, Mitra, Sahana, Roach, Finnegan D, Vasudevan, Deepika, Ryoo, Hyung Don
• Format: Article
• Language: English
• Subjects: Activating transcription factor 4; Animals; Animals, Genetically Modified; antioxidant response; Antioxidants; Antioxidants - metabolism; ATF4; Binding Sites; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; Drosophila melanogaster - embryology; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2 - metabolism; Gene expression; Gene Expression Regulation, Developmental; Genes; Genetic aspects; Genetics and Genomics; Glutathione; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Homeostasis; Imaginal Discs - embryology; Imaginal Discs - enzymology; Insects; Kinases; Open Reading Frames; PERK; Phosphorylation; Protein folding; Proteins; Rhodopsin - genetics; Rhodopsin - metabolism; Signal Transduction; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transferases; Unfolded Protein Response; Xrp1
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.74047

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 indicated that delta-family glutathione-S-transferases ( ) are prominently induced by the UPR-activating transgene was necessary and sufficient for such induction, but was not required. Instead, and other regulators of eIF2α phosphorylation regulated Xrp1 protein levels to induce . The 5' leader has a conserved upstream Open Reading Frame (uORF) analogous to those that regulate translation. The 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.