ZFIN ID: ZDB-PUB-081114-15
The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds
Kobayashi, M., Li, L., Iwamoto, N., Nakajima-Takagi, Y., Kaneko, H., Nakayama, Y., Eguchi, M., Wada, Y., Kumagai, Y., and Yamamoto, M.
Date: 2009
Source: Molecular and cellular biology   29(2): 493-502 (Journal)
Registered Authors: Kaneko, Hiroshi, Kobayashi, Makoto, Li, Li, Nakajima-Takagi, Yaeko, Yamamoto, Masayuki
Keywords: none
MeSH Terms:
  • Animals
  • Antioxidants
  • Carrier Proteins/chemistry
  • Carrier Proteins/metabolism*
  • Cysteine
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation
  • Glutathione S-Transferase pi/metabolism
  • Hydrogen Peroxide/pharmacology
  • Maleates/pharmacology
  • Mutation
  • NF-E2-Related Factor 2/metabolism*
  • Oxidative Stress
  • Prostaglandin D2/analogs & derivatives
  • Prostaglandin D2/pharmacology
  • Response Elements
  • Transcriptional Activation*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/metabolism*
PubMed: 19001094 Full text @ Mol. Cell. Biol.
Animals have evolved defense systems for surviving in a chemically diverse environment. Such systems should bear plasticity, like 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 eleven Nrf2-activating compounds. Firstly, 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. Secondly, 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 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.