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Molecular and Cellular Biology, June 2005, p. 4501-4513, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4501-4513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Keap1 Regulates the Oxidation-Sensitive Shuttling of Nrf2 into and out of the Nucleus via a Crm1-Dependent Nuclear Export Mechanism{dagger}

Michaella Velichkova* and Tama Hasson

Section of Cell and Developmental Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093

Received 9 August 2004/ Returned for modification 9 September 2004/ Accepted 24 February 2005

Keap1 is a negative regulator of Nrf2, a transcription factor essential for antioxidant response element (ARE)-mediated gene expression. We find that Keap1 sequesters Nrf2 in the cytoplasm, not by docking it to the actin cytoskeleton but instead through an active Crm1/exportin-dependent nuclear export mechanism. Deletion and mutagenesis studies identified a nuclear export signal (NES) in the intervening region of Keap1 comprised of hydrophobic leucine and isoleucine residues in agreement with a traditional NES consensus sequence. Mutation of the hydrophobic amino acids resulted in nuclear accumulation of both Keap1 and Nrf2, as did treatment with the drug leptomycin B, which inactivates Crm1/exportin. ARE genes were partially activated under these conditions, suggesting that additional oxidation-sensitive elements are required for full activation of the antioxidant response. Based on these data, we propose a new model for regulation of Nrf2 by Keap1. Under normal conditions, Keap1 and Nrf2 are complexed in the cytoplasm where they are targeted for degradation. Oxidative stress inactivates Keap1's NES, allowing entry of both Keap1 and Nrf2 into the nucleus and transcriptional transactivation of ARE genes.

* Corresponding author. Mailing address: University of California at San Diego, Division of Biological Sciences, Section of Cell and Developmental Biology, 2129 Bonner Hall, MC 0368, 9500 Gilman Drive, La Jolla, CA 92093-0368. Phone: (858) 822-3033. Fax: (858) 822-3034. E-mail: velichko{at}biomail.ucsd.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2005, p. 4501-4513, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4501-4513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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