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Molecular and Cellular Biology, January 2006, p. 221-229, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.221-229.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Oxidative and Electrophilic Stresses Activate Nrf2 through Inhibition of Ubiquitination Activity of Keap1{dagger}

Akira Kobayashi,1,2 Moon-Il Kang,1,3 Yoriko Watai,1 Kit I. Tong,1,3 Takahiro Shibata,4 Koji Uchida,4 and Masayuki Yamamoto1,2,3*

Center for Tsukuba Advanced Research Alliance,1 Graduate School of Comprehensive Human Sciences,2 JST-ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575,3 Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya 464-8601, Japan4

Received 11 July 2005/ Returned for modification 16 August 2005/ Accepted 16 October 2005

The Keap1-Nrf2 system is the major regulatory pathway of cytoprotective gene expression against oxidative and/or electrophilic stresses. Keap1 acts as a stress sensor protein in this system. While Keap1 constitutively suppresses Nrf2 activity under unstressed conditions, oxidants or electrophiles provoke the repression of Keap1 activity, inducing the Nrf2 activation. However, the precise molecular mechanisms behind the liberation of Nrf2 from Keap1 repression in the presence of stress remain to be elucidated. We hypothesized that oxidative and electrophilic stresses induce the nuclear accumulation of Nrf2 by affecting the Keap1-mediated rapid turnover of Nrf2, since such accumulation was diminished by the protein synthesis inhibitor cycloheximide. While both the Cys273 and Cys288 residues of Keap1 are required for suppressing Nrf2 nuclear accumulation, treatment of cells with electrophiles or mutation of these cysteine residues to alanine did not affect the association of Keap1 with Nrf2 either in vivo or in vitro. Rather, these treatments impaired the Keap1-mediated proteasomal degradation of Nrf2. These results support the contention that Nrf2 protein synthesized de novo after exposure to stress accumulates in the nucleus by bypassing the Keap1 gate and that the sensory mechanism of oxidative and electrophilic stresses is closely linked to the degradation mechanism of Nrf2.

* Corresponding author. Mailing address: Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan. Phone: 81-29-853-6158. Fax: 81-29-853-7318. E-mail: masi{at}tara.tsukuba.ac.jp.

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

Molecular and Cellular Biology, January 2006, p. 221-229, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.221-229.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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