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

  1. Brian Brown
  2. Sahana Mitra
  3. Finnegan D Roach
  4. Deepika Vasudevan
  5. Hyung Don Ryoo  Is a corresponding author
  1. 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.

The following data sets were generated

Article and author information

Author details

  1. Brian Brown

    NYU Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9826-4052
  2. Sahana Mitra

    NYU Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Finnegan D Roach

    NYU Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Deepika Vasudevan

    NYU Grossman School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hyung Don Ryoo

    NYU Grossman School of Medicine, New York, United States
    For correspondence
    hyungdon.ryoo@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1046-535X

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.

Reviewing Editor

  1. Julie Hollien, University of Utah, United States

Version history

  1. Received: September 20, 2021
  2. Accepted: September 27, 2021
  3. Accepted Manuscript published: October 4, 2021 (version 1)
  4. Version of Record published: October 13, 2021 (version 2)

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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  1. Brian Brown
  2. Sahana Mitra
  3. Finnegan D Roach
  4. Deepika Vasudevan
  5. Hyung Don Ryoo
(2021)
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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https://doi.org/10.7554/eLife.74047

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