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Molecular and Cellular Biology, October 2003, p. 7198-7209, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7198-7209.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Sara B. Cullinan,1 Donna Zhang,2 Mark Hannink,2 Edward Arvisais,3 Randal J. Kaufman,4 and J. Alan Diehl1*

The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104,1 Department of Biochemistry, University of Missouri—Columbia, Columbia Missouri,2 University of Nebraska Medical Center, Omaha, Nebraska 68198,3 Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 481094

Received 22 April 2003/ Returned for modification 28 May 2003/ Accepted 15 July 2003

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.

* Corresponding author. Mailing address: AFCRI, University of Pennsylvania Cancer Center 454 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-6389. Fax: (215) 746-5511. E-mail: adiehl{at}mail.med.upenn.edu.

Molecular and Cellular Biology, October 2003, p. 7198-7209, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7198-7209.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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