NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β-cells for protection.
NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β-cells for protection.
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NR4A1 抵消胰腺 β 细胞中 ER 应激或 ROS 引起的 JNK 激活以提供保护
DOI：
10.1111/jcmm.16028
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发表时间：
2020-12
影响因子：
5.3
通讯作者：
Wang XD
中科院分区：
文献类型：
--
作者：
Pu ZQ;Liu D;Lobo Mouguegue HPP;Jin CW;Sadiq E;Qin DD;Yu TF;Zong C;Chen JC;Zhao RX;Lin JY;Cheng J;Yu X;Li X;Zhang YC;Liu YT;Guan QB;Wang XD
持续的高血糖和高脂血症会导致胰腺β细胞内质网应激（ER应激）和活性氧（ROS）过量产生。内质网应激或ROS引起c - Jun N -末端激酶（JNK）激活，激活的JNK触发不同细胞的凋亡。核受体亚家族4A组成员1 （NR4A1）是一种诱导性的多逆境响应因子。本研究旨在探讨NR4A1在内质网应激或ROS诱导的JNK活化中的作用及其机制。采用qPCR、Western blotting、双荧光素酶报告基因和ChIP检测NR4A1基因的表达或调控。免疫荧光法检测β细胞中特异性蛋白的表达。我们的数据显示，NR4A1在遇到内质网应激或ROS的MIN6细胞中降低了磷酸化的JNK (p - JNK)，并以蛋白酶体依赖的方式降低了MKK4蛋白。我们发现NR4A1增加了cbl‐b （E3连接酶）的表达；在内质网应激或ROS条件下，抑制cbl‐b表达可增加MKK4和p‐JNK水平。我们发现NR4A1通过物理关联增强了cbl‐b启动子的转激活。我们进一步证实，与WT小鼠相比，NR4A1敲除小鼠β细胞中cbl - b的表达降低。NR4A1通过增强cbl - b表达下调β细胞内质网应激或ROS对JNK的激活。
Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic β‐cells. ER stress or ROS causes c‐Jun N‐terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi‐stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual‐luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in β‐cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p‐JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome‐dependent manner. We found that NR4A1 increased the expression of cbl‐b (an E3 ligase); knocking down cbl‐b expression increased MKK4 and p‐JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl‐b promoter by physical association. We further confirmed that cbl‐b expression in β‐cells was reduced in NR4A1‐knockout mice compared with WT mice. NR4A1 down‐regulates JNK activation by ER stress or ROS in β‐cells via enhancing cbl‐b expression.
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