RRC ID 70824
Author Brown B, Mitra S, Roach FD, Vasudevan D, Ryoo HD.
Title The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila.
Journal Elife
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 Drosophila indicated that delta-family glutathione-S-transferases (gstD) are prominently induced by the UPR-activating transgene Rh1G69D. Perk was necessary and sufficient for such gstD induction, but ATF4 was not required. Instead, Perk and other regulators of eIF2α 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.
Volume 10
Published 2021-10-4
DOI 10.7554/eLife.74047
PII 74047
PMID 34605405
PMC PMC8514241
MeSH Animals Animals, Genetically Modified Antioxidants / metabolism* Binding Sites DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / embryology Drosophila melanogaster / enzymology* Drosophila melanogaster / genetics Endoplasmic Reticulum Stress Eukaryotic Initiation Factor-2 / metabolism Gene Expression Regulation, Developmental Glutathione Transferase / genetics Glutathione Transferase / metabolism* Imaginal Discs / embryology Imaginal Discs / enzymology* Open Reading Frames Phosphorylation Rhodopsin / genetics Rhodopsin / metabolism Signal Transduction Transcription Factors / genetics Transcription Factors / metabolism Unfolded Protein Response eIF-2 Kinase / genetics eIF-2 Kinase / metabolism*
IF 7.08
Drosophila DGRC#142049 DGRC#105823