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ATF4-Dependent NRF2 Transcriptional Regulation Promotes Antioxidant Protection during Endoplasmic Reticulum Stress.


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.

SUBMITTER: Sarcinelli C 

PROVIDER: S-EPMC7139862 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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ATF4-Dependent <i>NRF2</i> Transcriptional Regulation Promotes Antioxidant Protection during Endoplasmic Reticulum Stress.

Sarcinelli Carmen C   Dragic Helena H   Piecyk Marie M   Barbet Virginie V   Duret Cédric C   Barthelaix Audrey A   Ferraro-Peyret Carole C   Fauvre Joelle J   Renno Toufic T   Chaveroux Cédric C   Manié Serge N SN  

Cancers 20200301 3


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 stimul  ...[more]

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