Abstract
Endoplasmic reticulum (ER) stress generates reactive oxygen species (ROS) that induce apoptosis if left unabated. To limit oxidative insults, the ER stress PKR-like endoplasmic reticulum Kinase (PERK) has been reported to phosphorylate and activate nuclear factor erythroid 2-related factor 2 (NRF2). Here, we uncover an alternative mechanism for PERK-mediated NRF2 regulation in human cells that does not require direct phosphorylation. We show that the activation of the PERK pathway rapidly stimulates the expression of NRF2 through activating transcription factor 4 (ATF4). In addition, NRF2 activation is late and largely driven by reactive oxygen species (ROS) generated during late protein synthesis recovery, contributing to protecting against cell death. Thus, PERK-mediated NRF2 activation encompasses a PERK-ATF4-dependent control of NRF2 expression that contributes to the NRF2 protective response engaged during ER stress-induced ROS production.
Highlights
The endoplasmic reticulum (ER) orchestrates protein folding and export
In order to investigate PKR-like endoplasmic reticulum Kinase (PERK)-activating transcription factor 4 (ATF4)-dependent regulation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response, which can be activated by inositol requiring enzyme 1 (IRE1) [7], we exclusively triggered the PERK pathway uncoupled from the other arms of the unfolded protein response (UPR) to provide a simplified cellular context
PERK activation triggers an ATF4-dependent control of NRF2 mRNA abundance that reinforces the cytoprotective function of NRF2
Summary
The endoplasmic reticulum (ER) orchestrates protein folding and export. This function is sensitive to cellular alterations in energy levels, redox status, or calcium homeostasis [1], resulting in accumulation of misfolded proteins in the ER lumen, a condition known as ER stress [2]. (IRE1) and activating transcription factor 6 (ATF6), which trigger the unfolded protein response (UPR). The UPR induces global translational and transcriptional changes to improve the ER protein-folding capacity. Activated PERK phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) that reduces protein synthesis but paradoxically increases the translation of mRNAs such as that of ATF4. ATF4 in turn initiates a transcriptional program including the up-regulation of the transcription factor C/EBP homologous protein (CHOP).
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