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Molecular and Cellular Biology, January 2009, p. 493-502, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01080-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds{triangledown} ,{dagger}

Makoto Kobayashi,1,2* Li Li,2 Noriko Iwamoto,3 Yaeko Nakajima-Takagi,2 Hiroshi Kaneko,2 Yuko Nakayama,1 Masami Eguchi,1 Yoshiko Wada,1 Yoshito Kumagai,3 and Masayuki Yamamoto1,4

ERATO Environmental Response Project, Japan Science and Technology Agency,1 Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan,2 Institute of Community Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan,3 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan4

Received 9 July 2008/ Returned for modification 3 September 2008/ Accepted 28 October 2008

Animals have evolved defense systems for surviving in a chemically diverse environment. Such systems should demonstrate plasticity, such as adaptive immunity, enabling a response to even unknown chemicals. The antioxidant transcription factor Nrf2 is activated in response to various electrophiles and induces cytoprotective enzymes that detoxify them. We report here the discovery of a multiple sensing mechanism for Nrf2 activation using zebrafish and 11 Nrf2-activating compounds. First, we showed that six of the compounds tested specifically target Cys-151 in Keap1, the ubiquitin ligase for Nrf2, while two compounds target Cys-273. Second, in addition to Nrf2 and Keap1, a third factor was deemed necessary for responding to three of the compounds. Finally, we isolated a zebrafish mutant defective in its response to seven compounds but not in response to the remaining four. These results led us to categorize Nrf2 activators into six classes and hypothesize that multiple sensing allows enhanced plasticity in the system.

* Corresponding author. Mailing address: Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. Phone: 81-29-853-8457. Fax: 81-29-853-5977. E-mail: makobayash{at}md.tsukuba.ac.jp

{triangledown} Published ahead of print on 11 November 2008.

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

Molecular and Cellular Biology, January 2009, p. 493-502, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01080-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • He, X., Ma, Q. (2009). NRF2 Cysteine Residues Are Critical for Oxidant/Electrophile-Sensing, Kelch-Like ECH-Associated Protein-1-Dependent Ubiquitination-Proteasomal Degradation, and Transcription Activation. Mol. Pharmacol. 76: 1265-1278 [Abstract] [Full Text]  


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