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

TLDR

PERK activation during ER stress inhibits translation and arrests the cell cycle, is essential for cell survival, yet the mechanisms remain unclear; in unstressed cells, Nrf2 is retained in the cytoplasm by Keap1. The study aims to uncover how PERK signaling promotes cell survival under ER stress. PERK activation is both necessary and sufficient to dissociate Nrf2/Keap1 complexes and drive Nrf2 nuclear import. We found that PERK phosphorylates Nrf2, triggering its release from Keap1 and nuclear translocation, and that Nrf2 loss heightens ER‑stress‑induced cell death, confirming Nrf2 as a critical effector of PERK‑mediated 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.