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KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease.
Open Biology ( IF 5.8 ) Pub Date : 2020-06-24 , DOI: 10.1098/rsob.200105
Sharadha Dayalan Naidu 1 , Albena T Dinkova-Kostova 1, 2
Affiliation  

Redox imbalance and persistent inflammation are the underlying causes of most chronic diseases. Mammalian cells have evolved elaborate mechanisms for restoring redox homeostasis and resolving acute inflammatory responses. One prominent mechanism is that of inducing the expression of antioxidant, anti-inflammatory and other cytoprotective proteins, while also suppressing the production of pro-inflammatory mediators, through the activation of transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2). At homeostatic conditions, NRF2 is a short-lived protein, which avidly binds to Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 functions as (i) a substrate adaptor for a Cullin 3 (CUL3)-based E3 ubiquitin ligase that targets NRF2 for ubiquitination and proteasomal degradation, and (ii) a cysteine-based sensor for a myriad of physiological and pharmacological NRF2 activators. Here, we review the intricate molecular mechanisms by which KEAP1 senses electrophiles and oxidants. Chemical modification of specific cysteine sensors of KEAP1 results in loss of NRF2-repressor function and alterations in the expression of NRF2-target genes that encode large networks of diverse proteins, which collectively restore redox balance and resolve inflammation, thus ensuring a comprehensive cytoprotection. We focus on the cyclic cyanoenones, the most potent NRF2 activators, some of which are currently in clinical trials for various pathologies characterized by redox imbalance and inflammation.

中文翻译:

KEAP1,一种基于半胱氨​​酸的传感器,是预防和治疗慢性疾病的药物靶标。

氧化还原失衡和持续性炎症是大多数慢性疾病的根本原因。哺乳动物细胞已经发展出完善的机制来恢复氧化还原稳态并解决急性炎症反应。一种突出的机制是通过激活转录因子核因子-类红细胞2 p45相关因子2(NRF2)来诱导抗氧化剂,抗炎蛋白和其他细胞保护性蛋白的表达,同时还抑制促炎性介质的产生。 。在体内平衡条件下,NRF2是一种短暂的蛋白质,可以与像Kelch一样的ECH相关蛋白1(KEAP1)狂热结合。KEAP1充当(i)基于Cullin 3(CUL3)的E3泛素连接酶的底物衔接子,该酶靶向NRF2进行泛素化和蛋白酶体降解,(ii)一种基于半胱氨​​酸的传感器,用于多种生理和药理NRF2激活剂。在这里,我们回顾了KEAP1感应亲电试剂和氧化剂的复杂分子机制。对KEAP1的特定半胱氨酸传感器进行化学修饰会导致NRF2阻遏物功能丧失,NRF2靶基因的表达发生变化,这些基因编码各种蛋白质的大型网络,共同恢复氧化还原平衡并解决炎症,从而确保全面的细胞保护。我们专注于环状氰基烯酮,这是最有效的NRF2激活剂,其中一些目前正在针对以氧化还原失衡和炎症为特征的各种病理学进行临床试验。对KEAP1的特定半胱氨酸传感器进行化学修饰会导致NRF2阻遏物功能丧失,NRF2靶基因的表达发生变化,这些基因编码各种蛋白质的大型网络,共同恢复氧化还原平衡并解决炎症,从而确保全面的细胞保护。我们专注于环状氰基烯酮,这是最有效的NRF2激活剂,其中一些目前正在针对以氧化还原失衡和炎症为特征的各种病理学进行临床试验。对KEAP1的特定半胱氨酸传感器进行化学修饰会导致NRF2阻遏物功能丧失,NRF2靶基因的表达发生变化,这些基因编码各种蛋白质的大型网络,共同恢复氧化还原平衡并解决炎症,从而确保全面的细胞保护。我们专注于环状氰基烯酮,这是最有效的NRF2激活剂,其中一些目前正在针对以氧化还原失衡和炎症为特征的各种病理学进行临床试验。
更新日期:2020-06-24
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