The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2.
The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2.
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DOI：
10.1016/j.isci.2021.103703
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发表时间：
2022-01-21
期刊：
影响因子：
5.8
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
--
作者：
Dayalan Naidu S;Suzuki T;Dikovskaya D;Knatko EV;Higgins M;Sato M;Novak M;Villegas JA;Moore TW;Yamamoto M;Dinkova-Kostova AT
转录因子Nrf2及其负调控因子Keap1协调对氧化、代谢和炎症应激的细胞保护反应。Keap1是一个药物靶点，有几个小分子正在药物开发中。在这里，我们证明了异喹啉PRL-295提高了细胞表达荧光标记的Keap1的裂解物中Keap1的热稳定性。在PRL-295处理后，内源性Keap1在完整细胞和小鼠肝脏中的热稳定性也增加。在共表达sfGFP-Nrf2和Keap1-mCherry的细胞中进行的荧光寿命成像-Förster共振能量转移(Flim-FRET)实验进一步表明，PRL-295延长了供体荧光寿命，表明Keap1-Nrf2蛋白复合体被破坏。小鼠口服PRL-295后，肝脏中Nrf2转录靶标NAD(P)H：Quone氧化还原酶1(NQO1)活性升高，血浆丙氨酸氨基转移酶和天冬氨酸转氨酶水平降低。因此，PRL-295在细胞和体内与Keap1蛋白靶标结合，破坏其与Nrf2的相互作用，导致Nrf2依赖的转录激活和肝细胞保护。PRL-295提高Keap1在细胞和小鼠肝脏中的热稳定性PRL-295破坏单个活细胞中Keap1-Nrf2蛋白复合体口服PRL-295激活小鼠肝脏中Nrf2转录靶点NQO1口服PRL-295小鼠口服PRL-295减轻对乙酰氨基酚诱导的肝损伤
Transcription factor Nrf2 and its negative regulator Keap1 orchestrate a cytoprotective response against oxidative, metabolic, and inflammatory stress. Keap1 is a drug target, with several small molecules in drug development. Here, we show that the isoquinoline PRL-295 increased Keap1 thermostability in lysates from cells expressing fluorescently tagged Keap1. The thermostability of endogenous Keap1 also increased in intact cells and murine liver following PRL-295 treatment. Fluorescence Lifetime Imaging–Förster Resonance Energy Transfer (FLIM-FRET) experiments in cells co-expressing sfGFP-Nrf2 and Keap1-mCherry further showed that PRL-295 prolonged the donor fluorescence lifetime, indicating disruption of the Keap1-Nrf2 protein complex. Orally administered PRL-295 to mice activated the Nrf2transcriptional target NAD(P)H:quinone oxidoreductase 1 (NQO1) in liver and decreased the levels of plasma alanine aminotransferase and aspartate aminotransferase upon acetaminophen-induced hepatic injury. Thus, PRL-295 engages the Keap1 protein target in cells and in vivo, disrupting its interaction with Nrf2, leading to activation of Nrf2-dependent transcription and hepatocellular protection. PRL-295 increases the thermostability of Keap1 in cells and in the murine liver PRL-295 disrupts the Keap1-Nrf2 protein complex in single live cells Orally administered PRL-295 activates the Nrf2 transcriptional target NQO1 in murine liver Orally administered PRL-295 to mice decreases acetaminophen-induced hepatic injury Biological sciences; Biochemistry; Molecular interaction
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影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
DOI：
10.1073/pnas.1305687110
发表时间：
2013-09-17
影响因子：
11.1
作者：
Baird, Liam;Lleres, David;Dinkova-Kostova, Albena T.
通讯作者：
Dinkova-Kostova, Albena T.
影响因子：
5.8
作者：
Knatko EV;Tatham MH;Zhang Y;Castro C;Higgins M;Dayalan Naidu S;Leonardi C;de la Vega L;Honda T;Griffin JL;Hay RT;Dinkova-Kostova AT
通讯作者：
Dinkova-Kostova AT
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
鉴定一种新型小分子 Keap1-Nrf2 PPI 抑制剂，对 LPS 诱导的心肌病具有细胞保护作用
DOI：
10.1080/14756366.2018.1461856
发表时间：
2018-12
影响因子：
5.6
作者：
Jiang CS;Zhuang CL;Zhu K;Zhang J;Muehlmann LA;Figueiró Longo JP;Azevedo RB;Zhang W;Meng N;Zhang H
通讯作者：
Zhang H