Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival

Sara B. Cullinan, Donna Zhang, Mark Hannink, Edward Arvisais, Randal J. Kaufman, J. Alan Diehl

Research output: Contribution to journalArticle

719 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7198-7209
Number of pages12
JournalMolecular and Cellular Biology
Volume23
Issue number20
DOIs
StatePublished - Oct 2003
Externally publishedYes

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Cell Survival
Endoplasmic Reticulum Stress
Unfolded Protein Response
Protein Unfolding
Cell Nucleus Active Transport
Cell Cycle Checkpoints
Endoplasmic Reticulum
Cytoplasm
Cell Death
Transcription Factors
Phosphorylation
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. / Cullinan, Sara B.; Zhang, Donna; Hannink, Mark; Arvisais, Edward; Kaufman, Randal J.; Diehl, J. Alan.

In: Molecular and Cellular Biology, Vol. 23, No. 20, 10.2003, p. 7198-7209.

Research output: Contribution to journalArticle

Cullinan, Sara B. ; Zhang, Donna ; Hannink, Mark ; Arvisais, Edward ; Kaufman, Randal J. ; Diehl, J. Alan. / Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 20. pp. 7198-7209.
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