C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape

Sharadha Dayalan Naidu, Aki Muramatsu, Ryota Saito, Soichiro Asami, Tadashi Honda, Tomonori Hosoya, Ken Itoh, Masayuki Yamamoto, Takafumi Suzuki, Albena Dinkova-Kostova (Lead / Corresponding author)

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    Abstract

    Numerous small molecules (termed inducers), many of which are electrophiles, upregulate cytoprotective responses and inhibit pro-inflammatory pathways by activating nuclear factor-erythroid 2 p45-related factor 2 (NRF2). Key to NRF2 activation is the ability to chemically modifying critical sensor cysteines in the main negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), of which C151, C273 and C288 are best characterized. This study aimed to establish the requirement for these cysteine sensor(s) for the biological activities of the most potent NRF2 activators known to date, the cyclic cyanoenones, some of which are in clinical trials. It was found that C151 in KEAP1 is the main cysteine sensor for this class of inducers, irrespective of molecular size or shape. Furthermore, in primary macrophage cells expressing C151S mutant KEAP1, at low concentrations, the tricyclic cyanoenone TBE-31 is inactive as an activator of NRF2 as well as an inhibitor of lipopolysaccharide-stimulated gene expression of the pro-inflammatory cytokines IL6 and IL1β. However, at high inducer concentrations, NRF2 activation proceeds in the absence of C151, albeit at a lower magnitude. Our findings highlight the intrinsic flexibility of KEAP1 and emphasize the critical importance of establishing the precise dose of NRF2 activators for maintaining on-target selectivity.
    Original languageEnglish
    Article number8037
    Pages (from-to)1-12
    Number of pages12
    JournalScientific Reports
    Volume8
    Issue number1
    DOIs
    Publication statusPublished - 23 May 2018

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    Keywords

    • Mechanism of action
    • Pharmacology

    Cite this

    Dayalan Naidu, S., Muramatsu, A., Saito, R., Asami, S., Honda, T., Hosoya, T., Itoh, K., Yamamoto, M., Suzuki, T., & Dinkova-Kostova, A. (2018). C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape. Scientific Reports, 8(1), 1-12. [8037]. https://doi.org/10.1038/s41598-018-26269-9