The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics.
The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics.
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DOI：
10.1042/bst20150003
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发表时间：
2015-08
影响因子：
3.9
通讯作者：
Abramov AY
中科院分区：
文献类型：
--
作者：
Dinkova-Kostova AT;Baird L;Holmström KM;Meyer CJ;Abramov AY
kelch样ECH相关蛋白1 (Keap1) -NF-E2 p45相关因子2 （Nrf2）通路调节防止氧化剂、亲电试剂和错误折叠蛋白累积损伤的蛋白质网络。转录因子Nrf2与其主要的负性细胞质调节因子Keap1之间的相互作用遵循一个循环，蛋白质复合物依次采用两种构象：“开放”，Nrf2与Keap1的一个单体结合，然后是“封闭”，Nrf2与Keap1二聚体的两个成员相互作用。亲电试剂和氧化剂（诱导剂）被Keap1内的半胱氨酸传感器识别，破坏其靶向Nrf2泛素化和降解的能力。因此，蛋白质复合物以“封闭”构象积累，游离的Keap1不能再生，新合成的Nrf2被稳定以激活靶基因转录。Keap1-Nrf2通路存在大量实验证据，普遍观点认为它位于细胞防御的核心，在应激条件下的适应和生存中起着至关重要的作用。最近，Nrf2在中间代谢和线粒体生理中的重要性也被认识到，为Nrf2的功能库增加了另一层细胞保护。Nrf2影响线粒体活性的一种方式是通过增加呼吸底物（NADH和FADH2）的可用性。另一种方法是通过加速脂肪酸氧化（粮农组织）。这些发现强化了氧化磷酸化和细胞氧化还原状态之间的相互关系，并强调了Nrf2在调节这种平衡中的关键作用。
The Kelch-like ECH associated protein 1 (Keap1)–NF-E2 p45-related factor 2 (Nrf2) pathway regulates networks of proteins that protect against the cumulative damage of oxidants, electrophiles and misfolded proteins. The interaction between transcription factor Nrf2 and its main negative cytoplasmic regulator Keap1 follows a cycle whereby the protein complex sequentially adopts two conformations: ‘open’, in which Nrf2 binds to one monomer of Keap1, followed by ‘closed’, in which Nrf2 interacts with both members of the Keap1 dimer. Electrophiles and oxidants (inducers) are recognized by cysteine sensors within Keap1, disrupting its ability to target Nrf2 for ubiquitination and degradation. Consequently, the protein complex accumulates in the ‘closed’ conformation, free Keap1 is not regenerated and newly synthesized Nrf2 is stabilized to activate target-gene transcription. The prevailing view of the Keap1–Nrf2 pathway, for which there exists a wealth of experimental evidence, is that it lies at the heart of cellular defence, playing crucial roles in adaptation and survival under conditions of stress. More recently, the significance of Nrf2 in intermediary metabolism and mitochondrial physiology has also been recognized, adding another layer of cytoprotection to the repertoire of functions of Nrf2. One way by which Nrf2 influences mitochondrial activity is through increasing the availability of substrates (NADH and FADH2) for respiration. Another way is through accelerating fatty acid oxidation (FAO). These findings reinforce the reciprocal relationship between oxidative phosphorylation and the cellular redox state, and highlight the key role of Nrf2 in regulating this balance.