KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease

被引:82
作者
Dayalan Naidu, Sharadha [1 ]
Dinkova-Kostova, Albena T. [1 ,2 ,3 ]
机构
[1] Univ Dundee, Sch Med, Div Cellular Med, Jacqui Wood Canc Ctr, Dundee, Scotland
[2] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
关键词
KEAP1; NRF2; cysteine; anti-inflammatory; antioxidant; redox; TRANSCRIPTION FACTOR NRF2; HIGHLY-ACTIVE INHIBITORS; NITRIC-OXIDE PRODUCTION; CUL3-BASED E3 LIGASE; OXIDATIVE STRESS; PROTEASOMAL DEGRADATION; MOLECULAR-MECHANISM; TRICYCLIC COMPOUNDS; THERAPEUTIC TARGET; SYNTHETIC OLEANANE;
D O I
10.1098/rsob.200105
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:13
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