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

148 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)342-350
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume433
Issue number2
DOIs
Publication statusPublished - 2005 Jan 15
Externally publishedYes

Keywords

  • Degradation
  • Keap1
  • Nrf2
  • Proteasome
  • Ubiquitination

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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