Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2)

Wen Li, Hui Liu, Jie Sen Zhou, Jiao Fei Cao, Xiao Bo Zhou, Augustine M.K. Choi, Zhi Hua Chen, Hua Hao Shen

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

The Nrf2 (nuclear erythroid 2 p45-related factor-2) signaling pathway is known to play a pivotal role in a variety of oxidative stress-related human disorders. It has been reported recently that the plasma membrane resident protein caveolin-1 (Cav-1) can regulate expression of certain antioxidant enzymes and involves in the pathogenesis of oxidative lung injury, but the detailed molecular mechanisms remain incompletely understood. Here, we demonstrated that Cav-1 inhibited the expression of antioxidant enzymes through direct interaction with Nrf2 and subsequent suppression of its transcriptional activity in lung epithelial Beas-2B cells. Cav-1 deficiency cells exhibited higher levels of antioxidant enzymes and were more resistant to oxidative stress induced cytotoxicity, whereas overexpression of Cav-1 suppressed the induction of these enzymes and further augmented the oxidative cell death. Cav-1 constitutively interacted with Nrf2 in both cytosol and nucleus. Stimulation of 4-hydroxynonenol increased the Cav-1-Nrf2 interaction in cytosol but disrupted their association in the nucleus. Knockdown of Cav-1 also disassociated the interaction between Nrf2 and its cytoplasmic inhibitor Keap1 (Kelch-like ECH-associated protein 1) and increased the Nrf2 transcription activity. Mutation of the resembling Cav-1 binding motif on Nrf2 effectively attenuated their interaction, which exhibited higher transcription activity and induced higher levels of antioxidant enzymes relative to the wild-type control. Altogether, these studies clearly demonstrate that Cav-1 inhibits cellular antioxidant capacity through direct interaction with Nrf2 and subsequent suppression of its activity, thereby implicating in certain oxidative stress-related human pathologies.

Original languageEnglish (US)
Pages (from-to)20922-20930
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number25
DOIs
StatePublished - Jun 15 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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