Nrf2 Is a Direct PERK Substrate and Effector of PERK-Dependent Cell Survival

Abstract

Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER)promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate. In unstressed cells, Nrf2 is maintained in the cytoplasm via association with Keap1. PERK-dependent phosphorylation triggers dissociation of Nrf2/Keap1 complexes and inhibits reassociation of Nrf2/Keap1 complexes in vitro. Activation of PERK via agents that trigger the unfolded protein response is both necessary and sufficient for dissociation of cytoplasmic Nrf2/Keap1 and subsequent Nrf2 nuclear import. Finally, we demonstrate that cells harboring a targeted deletion of Nrf2 exhibit increased cell death relative to wild-type counterparts following exposure to ER stress. Our data demonstrate that Nrf2 is a critical effector of PERK-mediated cell survival.

Cellular response to endoplasmic reticulum stress: a matter of life or death

“…[126][127][128] Therefore, a loss of Nrf2 function may partly explain why PERK À/À cells experience increased oxidative stress in response to perturbations in ER function. 108 Consistent with this model, Nrf2 À/À cells are sensitized to ER stress, 125 providing another way in which PERK signaling promotes cell survival.…”

“…124 The bZIP transcription factor Nrf2 was recently identified as a second substrate of PERK. 125 Upon ESR induction, PERK phosphorylation causes Nrf2 to relocalize from the cytoplasm to the nucleus, where it upregulates a range of antioxidant response genes. [126][127][128] Therefore, a loss of Nrf2 function may partly explain why PERK À/À cells experience increased oxidative stress in response to perturbations in ER function.…”

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

“…However, very high concentrations of metformin (5 m m ) were required to observe significant inhibition of mitochondrion respiratory chain complex 1 activity (He & Wondisford, 2015). Recent studies showed that Nrf2 can be activated by the ER unfolded protein response sensors IRE1α (Hourihan, Moronetti Mazzeo, Fernandez‐Cardenas, & Blackwell, 2016) and PERK (Cullinan et al., 2003). However, in our hands, PERK activation was not detected when HDFs were treated with 100 μ m metformin (Fig.…”

Dynamics of unfolded protein response in recombinant CHO cells

“…NRF2 also induces the expression of anti-oxidant responsive genes (Chen and Kunsch 2004). This is possibly the response to high oxidative stress in these recombinant CHO cells as a result of continuous and repeated folding processes inside the stressed ER (Cullinan et al 2003).…”