The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila
- NYU Grossman School of Medicine, United States
Abstract
PERK is an endoplasmic reticulum (ER) transmembrane sensor that phosphorylates eIF2a to initiate the Unfolded Protein Response (UPR). eIF2a 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 eIF2a 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.
Data availability
Sequencing data have been deposited in GEO under the accession code GSE150058. Source Data files have been provided for Figures 2-6 and 8.
Article and author information
Author details
Funding
National Eye Institute (R01 EY020866)
- Hyung Don Ryoo
National Institute of General Medical Sciences (R01 GM125954)
- Hyung Don Ryoo
National Institute of General Medical Sciences (T32 GM136573)
- Brian Brown
Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32 HD007520)
- Brian Brown
National Eye Institute (K99 EY029013)
- Deepika Vasudevan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Brown et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila
eLife 10:e74047.
https://doi.org/10.7554/eLife.74047
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