The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in <i>Drosophila</i>.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34605405.
- Also identified by DOI 10.7554/eLife.74047 and PMC identifier 8514241.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>G69D</sup>. 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.
Medical subject headings
- Antioxidants
- DNA-Binding Proteins
- Drosophila Proteins
- Drosophila melanogaster
- Glutathione Transferase
- Imaginal Discs
- eIF-2 Kinase