Nuclear trapping of inactive FOXO1 by the Nrf2 activator diethyl maleate.
Nuclear trapping of inactive FOXO1 by the Nrf2 activator diethyl maleate.
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DOI：
10.1016/j.redox.2018.09.010
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Klotz LO
中科院分区：
文献类型：
--
作者：
Gille A;Turkistani A;Tsitsipatis D;Hou X;Tauber S;Hamann I;Urban N;Erler K;Steinbrenner H;Klotz LO
马来酸二乙酯（DEM）是一种巯基反应性α，β-不饱和羰基化合物，可耗尽暴露细胞中的谷胱甘肽（GSH），我们先前已证明，在秀丽隐杆线虫中引起应激反应，在较低浓度下，可增强抗应激能力并延长寿命。这种激素反应是通过Nrf 2的直系同源物SKN-1和叉头盒O（FOXO）家族转录因子β-16介导的。由于FOXO信号转导在进化上是保守的，我们在这里分析了DEM暴露对培养的人细胞（HepG 2，HEK 293）中FOXO的影响。DEM引起GFP偶联的野生型人FOXO 1以及半胱氨酸缺陷型FOXO 1突变体的核积累。尽管FOXO 1的核积累，既没有FOXO 1 DNA结合，也没有FOXO靶基因的表达被刺激，这表明DEM引起核积累，但没有激活FOXO 1。FOXO 1核排斥引起的胰岛素或外源性物质，如亚砷酸盐或铜离子被衰减DEM，这表明DEM干扰核输出。与FOXO依赖性基因表达不同，Nrf 2靶基因mRNA在DEM作用下升高。这些数据表明，与C. elegans，DEM eleventing相反的影响，两个应激反应转录因子，Nrf 2和FOXO 1，在培养的人类细胞。马来酸二乙酯（DEM）导致FOXO 1在HepG 2或HEK 293细胞中的核积聚。DEM还能解释FOXO同源基因B16在C.优雅然而，DEM不引起FOXO的表达，但Nrf 2靶基因的表达。胰岛素诱导的FOXO 1磷酸化和核排斥被DEM减弱。FOXO 1的核积聚是由于干扰核输出机制。
Diethyl maleate (DEM), a thiol-reactive α,β-unsaturated carbonyl compound, depletes glutathione (GSH) in exposed cells and was previously shown by us to elicit a stress response in Caenorhabditis elegans that, at lower concentrations, results in enhanced stress resistance and longer lifespan. This hormetic response was mediated through both the Nrf2 ortholog, SKN-1, and the forkhead box O (FOXO) family transcription factor DAF-16. As FOXO signaling is evolutionarily conserved, we analyzed here the effects of DEM exposure on FOXO in cultured human cells (HepG2, HEK293). DEM elicited nuclear accumulation of GFP-coupled wild-type human FOXO1, as well as of a cysteine-deficient FOXO1 mutant. Despite the nuclear accumulation of FOXO1, neither FOXO1 DNA binding nor FOXO target gene expression were stimulated, suggesting that DEM causes nuclear accumulation but not activation of FOXO1. FOXO1 nuclear exclusion elicited by insulin or xenobiotics such as arsenite or copper ions was attenuated by DEM, suggesting that DEM interfered with nuclear export. In addition, insulin-induced FOXO1 phosphorylation at Thr-24, which is associated with FOXO1 nuclear exclusion, was attenuated upon exposure to DEM. Different from FOXO-dependent expression of genes, Nrf2 target gene mRNAs were elevated upon exposure to DEM. These data suggest that, different from C. elegans, DEM elicits opposing effects on the two stress-responsive transcription factors, Nrf2 and FOXO1, in cultured human cells. Diethyl maleate (DEM) causes FOXO1 nuclear accumulation in HepG2 or HEK293 cells. DEM also elicits nuclear accumulation of the FOXO-ortholog, DAF-16, in C. elegans. Nevertheless, DEM does not elicit expression of FOXO, but of Nrf2 target genes. Insulin-induced FOXO1 phosphorylation and nuclear exclusion are attenuated by DEM. Nuclear accumulation of FOXO1 is due to interference with nuclear export machinery.
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