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

Sharadha Dayalan Naidu, Albena Dinkova-Kostova (Lead / Corresponding author)

    Research output: Contribution to journalReview articlepeer-review

    70 Citations (Scopus)
    116 Downloads (Pure)

    Abstract

    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.

    Original languageEnglish
    Article number200105
    Number of pages13
    JournalOpen Biology
    Volume10
    Issue number6
    Early online date24 Jun 2020
    DOIs
    Publication statusPublished - Jun 2020

    Keywords

    • KEAP1
    • NRF2
    • cysteines
    • chronic disease
    • prevention
    • anti-inflammatory
    • antioxidant
    • redox
    • oxidative stress
    • cysteine

    ASJC Scopus subject areas

    • General Biochemistry,Genetics and Molecular Biology
    • General Neuroscience
    • Immunology

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