Caveolin-1 Inhibits Expression of Antioxidant Enzymes through Direct Interaction with Nuclear Erythroid 2 p45-related Factor-2 (Nrf2)
Caveolin-1 Inhibits Expression of Antioxidant Enzymes through Direct Interaction with Nuclear Erythroid 2 p45-related Factor-2 (Nrf2)
复制标题
Caveolin-1 通过与核红细胞 2 p45 相关因子 2 (Nrf2) 直接相互作用抑制抗氧化酶的表达
DOI：
10.1074/jbc.m112.352336
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发表时间：
2012-06-15
影响因子：
4.8
通讯作者：
Shen, Hua-Hao
中科院分区：
文献类型：
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作者：
Li, Wen;Liu, Hui;Shen, Hua-Hao
Nrf2（核红细胞2 p45相关因子-2）信号通路在多种氧化应激相关的人类疾病中发挥关键作用。近年来有报道称，质膜驻留蛋白Cav-1可以调控某些抗氧化酶的表达，参与肺氧化损伤的发病机制，但其具体的分子机制尚不完全清楚。在这里，我们证明了Cav-1通过直接与Nrf2相互作用并随后抑制其在肺上皮Beas-2B细胞中的转录活性来抑制抗氧化酶的表达。Cav-1缺乏的细胞表现出更高水平的抗氧化酶，对氧化应激诱导的细胞毒性更有抵抗力，而Cav-1过表达抑制了这些酶的诱导，进一步增加了氧化细胞死亡。Cav-1在细胞质和细胞核中均与Nrf2相互作用。4-羟基壬烯醇的刺激增加了细胞质中Cav-1-Nrf2的相互作用，但破坏了它们在细胞核中的相互作用。Cav-1的敲除还解除了Nrf2与其细胞质抑制剂Keap1 （Kelch-like ECH-associated protein 1）之间的相互作用，并增加了Nrf2的转录活性。与野生型对照相比，Nrf2上类似Cav-1结合基序的突变有效地减弱了它们之间的相互作用，表现出更高的转录活性，并诱导出更高的抗氧化酶水平。总之，这些研究清楚地表明，Cav-1通过直接与Nrf2相互作用并随后抑制其活性来抑制细胞抗氧化能力，从而暗示某些氧化应激相关的人类病理。
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. Knock-down 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.