Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome

Yasutake Katoh, Katsuyuki Iida, Moon-Il Kang, Akira Kobayashi, Mio Mizukami, Kit I. Tong, Michael McMahon, John D. Hayes, Ken Itoh, Masayuki Yamamoto

    Research output: Contribution to journalArticlepeer-review

    159 Citations (Scopus)

    Abstract

    Under homeostatic conditions, Nrf2 activity is constitutively repressed. This process is dependent on Keap1, to which Nrf2 binds through the Neh2 domain. Since the N-terminal subdomain of Neh2 (Neh2-NT) contains evolutionarily conserved motifs, we examined the roles they play in the degradation of Nrf2. In Neh2-NT, we defined a novel motif that is distinct from the previously characterized DIDLID motif and designated it DLG motif. Deletion of Neh2-NT or mutation of the DLG motif largely abolished the Keap1-mediated degradation of Nrf2. These mutations were found to enfeeble the binding affinity of Nrf2 to Keap1. The Neh2-NT subdomain directed DLG-dependent, Keap1-independent, degradation of a reporter protein in the nucleus. By contrast, mutation of DLG did not affect the half-life of native Nrf2 protein in the nucleus under oxidative stress conditions. These results thus demonstrate that DLG motif plays essential roles in the Keap1-mediated proteasomal degradation of Nrf2 in the cytoplasm.
    Original languageEnglish
    Pages (from-to)342-50
    Number of pages9
    JournalArchives of Biochemistry and Biophysics
    Volume433
    Issue number2
    DOIs
    Publication statusPublished - 2005

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