title: Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2).
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.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Jie-Sen
authors.initials: JS
authors.lastname: Zhou
authors.forename: Jiao-Fei
authors.initials: JF
authors.lastname: Cao
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhou
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; C495540:CAV1 protein, human; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse