The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds

Makoto Kobayashi, Li Li, Noriko Iwamoto, Yaeko Nakajima-Takagi, Hiroshi Kaneko, Yuko Nakayama, Masami Eguchi, Yoshiko Wada, Yoshito Kumagai, Masayuki Yamamoto

研究成果: Article査読

496 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)493-502
ページ数10
ジャーナルMolecular and cellular biology
29
2
DOI
出版ステータスPublished - 2009 1月

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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