The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds.
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.
Kobayashi
Makoto
M
ERATO Environmental Response Project, Japan Science and Technology Agency, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. makobayash@md.tsukuba.ac.jp
Li
Li
L
Iwamoto
Noriko
N
Nakajima-Takagi
Yaeko
Y
Kaneko
Hiroshi
H
Nakayama
Yuko
Y
Eguchi
Masami
M
Wada
Yoshiko
Y
Kumagai
Yoshito
Y
Yamamoto
Masayuki
M
D000818:Animals; D000975:Antioxidants; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008298:Maleates / Q000494:pharmacology; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D020218:Response Elements; D015533:Transcriptional Activation; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000975:Antioxidants; D002352:Carrier Proteins; C527640:Keap1a protein, zebrafish; C527641:Keap1b protein, zebrafish; D008298:Maleates; D051267:NF-E2-Related Factor 2; D029961:Zebrafish Proteins; C495638:nfe2l2a protein, zebrafish; D006861:Hydrogen Peroxide; D051549:Glutathione S-Transferase pi; C014476:diethyl maleate; D003545:Cysteine; D015230:Prostaglandin D2