The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila
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 PER...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2021-10-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/74047 |
| _version_ | 1797998429429825536 |
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| author | Brian Brown Sahana Mitra Finnegan D Roach Deepika Vasudevan Hyung Don Ryoo |
| author_facet | Brian Brown Sahana Mitra Finnegan D Roach Deepika Vasudevan Hyung Don Ryoo |
| author_sort | Brian Brown |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:48:37Z |
| format | Article |
| id | doaj.art-3871a8bb819e4fc58256c93679f7d1b9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:48:37Z |
| publishDate | 2021-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3871a8bb819e4fc58256c93679f7d1b92022-12-22T04:28:58ZengeLife Sciences Publications LtdeLife2050-084X2021-10-011010.7554/eLife.74047The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in DrosophilaBrian Brown0https://orcid.org/0000-0001-9826-4052Sahana Mitra1https://orcid.org/0000-0001-8339-1307Finnegan D Roach2https://orcid.org/0000-0002-4214-2002Deepika Vasudevan3Hyung Don Ryoo4https://orcid.org/0000-0002-1046-535XNYU Grossman School of Medicine, New York, United StatesNYU Grossman School of Medicine, New York, United StatesNYU Grossman School of Medicine, New York, United StatesNYU Grossman School of Medicine, New York, United StatesNYU Grossman School of Medicine, New York, United StatesPERK 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.https://elifesciences.org/articles/74047unfolded protein responseantioxidant responsePERKXrp1ATF4Drosophila |
| spellingShingle | Brian Brown Sahana Mitra Finnegan D Roach Deepika Vasudevan Hyung Don Ryoo The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila eLife unfolded protein response antioxidant response PERK Xrp1 ATF4 Drosophila |
| title | The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila |
| title_full | The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila |
| title_fullStr | The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila |
| title_full_unstemmed | The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila |
| title_short | The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila |
| title_sort | transcription factor xrp1 is required for perk mediated antioxidant gene induction in drosophila |
| topic | unfolded protein response antioxidant response PERK Xrp1 ATF4 Drosophila |
| url | https://elifesciences.org/articles/74047 |
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