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

TLDR

Animals have evolved chemically diverse defense systems that exhibit plasticity, such as adaptive immunity, enabling responses to unknown chemicals, exemplified by the antioxidant transcription factor Nrf2, which is activated by electrophiles to induce cytoprotective enzymes. The study aims to uncover a multiple‑sensing mechanism for Nrf2 activation by testing 11 Nrf2‑activating compounds in zebrafish. Using zebrafish as a model, the authors screened 11 Nrf2‑activating compounds to identify distinct cysteine targets and additional factors involved in activation. They found that six compounds target Keap1 Cys‑151, two target Cys‑273, a third factor is required for three compounds, a zebrafish mutant lacks response to seven compounds, leading to classification of activators into six classes and supporting a hypothesis that multiple sensing enhances system plasticity.

Abstract

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.