Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1
Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1
复制标题
DOI：
10.1016/j.celrep.2019.06.047
复制
发表时间：
2019-07-16
期刊：
影响因子：
8.8
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Suzuki, Takafumi;Muramatsu, Aki;Yamamoto, Masayuki
Keap 1-Nrf 2系统在氧化应激反应中起着核心作用;然而，Keap 1内活性氧传感器的身份仍然知之甚少。在这里，我们表明，缺乏11个半胱氨酸残基的Keap 1突变体保留了靶向Nrf 2降解的能力，但它无法响应半胱氨酸反应性Nrf 2诱导剂。在11个突变的半胱氨酸残基中，我们发现4个（Cys 226/613/622/624）对于感测过氧化氢是重要的。我们对多个突变小鼠系的分析，以及对表达一系列Keap 1突变体的MEFs的分析，揭示了Keap 1冗余地使用半胱氨酸残基来建立一种精心设计的故障安全机制，其中这四个半胱氨酸残基的特定组合可以形成二硫键来检测过氧化氢。这种传感机制与用于亲电子Nrf 2诱导剂的传感机制不同，表明Keap 1配备了多个基于半胱氨酸的传感器来检测各种内源性和外源性应激。
The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.