C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape.
C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape.
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DOI：
10.1038/s41598-018-26269-9
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发表时间：
2018-05-23
影响因子：
4.6
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
--
作者：
Dayalan Naidu S;Muramatsu A;Saito R;Asami S;Honda T;Hosoya T;Itoh K;Yamamoto M;Suzuki T;Dinkova-Kostova AT
许多小分子(称为诱导剂)，其中许多是亲电性的，通过激活核因子-红系P45相关因子2(NRF2)上调细胞保护反应并抑制促炎途径。NRF2激活的关键是对NRF2的主要负调控因子Kelch样ECH相关蛋白1(Keap1)中关键传感器半胱氨酸进行化学修饰的能力，其中C151、C273和C288是最好的特征。本研究旨在确定这些半胱氨酸传感器(S)对已知的最有效的NRF2激活剂-环氰烯酮的生物活性的需求，其中一些正在进行临床试验。研究发现，无论分子大小或形状如何，Keap1中的C151是这类诱导剂的主要半胱氨酸传感器。此外，在表达C151S突变体Keap1的原代巨噬细胞中，三环氰烯酮Tbe-31在低浓度下既不能激活NRF2，也不能抑制内毒素刺激的促炎细胞因子IL6和IL1β的基因表达。然而，在高诱导剂浓度下，NRF2的激活在没有C151的情况下进行，尽管幅度较低。我们的发现突出了Keap1的内在灵活性，并强调了确定NRF2激活剂的准确剂量对于维持靶向选择性的关键重要性。
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.
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影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
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影响因子：
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DOI：
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发表时间：
2016-11-01
影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0500815102
发表时间：
2005-03-22
影响因子：
11.1
作者：
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通讯作者：
Talalay, P