Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway
Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway
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核因子 p65 与 Keap1 相互作用抑制 Nrf2-ARE 通路
DOI：
10.1016/j.cellsig.2011.01.014
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发表时间：
2011-05-01
影响因子：
4.8
通讯作者：
Yang, Xiaoming
中科院分区：
文献类型：
--
作者：
Yu, Miao;Li, Hui;Yang, Xiaoming
Keap1是Nrf2的抑制剂，参与Nrf2依赖的抗氧化反应。然而，Keap1如何调控Nrf2-ARE信号通路的机制尚不清楚。在这里，通过酵母双杂交技术，核因子-kappa B转录因子p65亚基被鉴定为Keap1的合作伙伴。我们发现Keap1在体内和体外都与p65有物理联系。P65的过表达可抑制顺丁烯二酸二乙酯(DEM)或叔丁基羟基苯二酚(TBHQ)诱导的Nrf2依赖转录。通过RNA干扰敲除Keap1部分阻断了p65对Nrf2介导的激活的抑制。结果表明，p65减少了Nrf2与其同源DNA序列的结合，增强了Nrf2的泛素化。P65的N-末端区域是与Keap1相互作用及其转录抑制活性所必需的。此外，Keap1的核转位增加了p65。综上所述，我们的研究结果提示，核因子-kappaB信号通过p65和Keap1的相互作用抑制Nrf2-ARE通路。(C)2011 Elsevier Inc.保留所有权利。
Keap1 is an inhibitor of Nrf2 involved in Nrf2-dependent antioxidant response. However, the mechanisms on how Keap1 regulates Nrf2-ARE signaling pathway remains to be determined. Here, by using a yeast two-hybrid technology, p65 subunit of NF-kappa B transcription factor was identified as a partner of Keap1. We show that Keap1 physically associated with p65 in vivo and in vitro. Overexpression of p65 inhibited Nrf2-dependent transcription induced by diethylmaleate (DEM) or tert-butyl hydroxyquinone (tBHQ). Knock down of Keap1 by RNA interference partially blocked the repression of Nrf2-mediated activation by p65. It was demonstrated that p65 decreased Nrf2 binding to its cognate DNA sequences and enhanced Nrf2 ubiquitination. The N-terminal region of p65 is necessary for both the interaction with Keap1 and its transcriptional suppression activity. Moreover, nuclear translocation of Keap1 was augmented by p65. Taken together, our findings suggest that NF-kappa B signaling inhibits Nrf2-ARE pathway through the interaction of p65 and Keap1. (C) 2011 Elsevier Inc. All rights reserved.