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J. Biol. Chem., Vol. 281, Issue 37, 27251-27263, September 15, 2006

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Nrf2 Possesses a Redox-sensitive Nuclear Exporting Signal in the Neh5 Transactivation Domain^*

From the Department of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854

NF-E2-related factor 2 (Nrf2) is the key transcription factor regulating the antioxidant response. Previous studies identified a nuclear localization signal (NLS) in the basic region and a nuclear exporting signal (NES) in the leucine zipper domain of Nrf2. In this study, we characterize a new functional NES (¹⁷⁵LLSIPELQCLNI¹⁸⁶) in the transactivation (TA) domain of Nrf2. A green fluorescence protein (GFP)-tagged Nrf2 segment (amino acids162-295) called GFP-NES_TA exhibited a cytosolic distribution that could be disrupted by L184A mutation or leptomycin B treatment. Chimeric expression of this NES_TA with a nuclear protein GAL4DBD could expel GAL4DBD into the cytoplasm. A variety of oxidants, including sulforaphane, tert-butylhydroquinone, and H₂O₂, could effectively induce nuclear translocation of GFP-NES_TA. Mutational studies showed that cysteine 183 may mediate the redox response of NES_TA. The discovery of multiple NLS/NES motifs in Nrf2 and the redox sensitivity of NES_TA imply Nrf2 may be self-sufficient to sense and transduce oxidative signals into the nucleus, consequently initiating antioxidant gene transcription.

Received for publication, March 23, 2006 , and in revised form, June 6, 2006.

^* This work was supported by National Institutes of Health Grant R01 CA94828 (to A.-N. T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Rd., Piscataway, NJ 08854. Tel.: 732-445-3831 (ext. 228); Fax: 732-445-3134; E-mail: KongT{at}rci.rutgers.edu.

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