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.

Transcriptional Changes Involved in Atrophying Muscles during Prolonged Fasting in Rats

“…Its increased gene expression ( Figure 6 ), together with increased mRNA levels for its coworkers, Keap1 , and the small Maf proteins ( Maff , Mafg , and Mafk ), as well as downregulation of the inhibitory musculoaponeurotic fibrosarcoma oncogene (cMaf) transcription factor ( Maf ) [ 91 ], argue for a role of NRF2 in inducing gene expression of antioxidant enzymes during P2 and especially P3 of fasting, including Hmox1 , Sod1 , catalase , Gpx3 , and most of Gsts . Interestingly, phosphorylation is not the only activating pathway for NRF2, and a role for ATF4 has been recently reported [ 92 ]. ATF4, ATF6, ERN1, and HSPA5 are major factors in the response to ER stress [ 93 ].…”

Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union

“…Additionally, PERK also directly phosphorylates NRF2, regulating the antioxidant response by nullifying the ROS production during ER stress in fibroblasts (34). Recent investigations, however, direct toward an alternative NRF2 regulation in response to oxidative stress via PERK-eIF2a-ATF4 axis in human cells (NCI-H358) (35).…”

Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer

“…Similar to IRE1, PERK dimerizes and trans-autophosphorylates upon ER stress [229]. PERK upregulates the transcription factor Nrf2 through ATF4 [230] and phosphorylates it [231,232], leading, in particular, to the expression of proteins aimed at restoring redox homeostasis. PERK also phosphorylates eIF2α, at S51, leading to an overall decrease in translation but also to an increase in specific protein translation, e.g., of ATF4.…”

“…For example, the Strasser's laboratory demonstrated early on that Bim is required for ER-stress-induced cell death in multiple cell lines and highlighted that ER stress activates Bim through Protein Phosphatase 2A (PP2A)-mediated dephosphorylation, preventing Bim degradative ubiquitination; and through CHOP-dependent Similar to IRE1, PERK dimerizes and trans-autophosphorylates upon ER stress [229]. PERK up-regulates the transcription factor Nrf2 through ATF4 [230] and phosphorylates it [231,232], leading, in particular, to the expression of proteins aimed at restoring redox homeostasis. PERK also phosphorylates eIF2α, at S51, leading to an overall decrease in translation but also to an increase in specific protein translation, e.g., of ATF4.…”