DDIT4 S-Nitrosylation Aids p38-MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production,Advanced Science

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DDIT4 S-Nitrosylation Aids p38-MAPK Signaling Complex Assembly to Promote Hepatic Reactive Oxygen Species Production
Advanced Science ( IF 14.3 ) Pub Date : 2021-07-26 , DOI: 10.1002/advs.202101957
Zilong Li _{1,

2,

3,

4} , Qianwen Zhao ₄ , Yunjie Lu ₁ , Yangxi Zhang ₂ , Luyang Li ₂ , Min Li ₂ , Xuemin Chen ₁ , Donglin Sun ₁ , Yunfei Duan ₁ , Yong Xu _{2,

3,

4}

Affiliation

Mitogen-activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma-related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage-induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38-MAPK signaling complex to drive ROS production in an S-nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4-inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38-MAPK signaling, and ameliorate liver injury by influencing DDIT4 S-nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S-nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription-based signaling cascade that contributes to ROS production in liver injury.

中文翻译：

DDIT4 S-亚硝基化有助于 p38-MAPK 信号复合物组装，促进肝脏活性氧的产生

丝裂原激活蛋白激酶 (MAPK) 信号在活性氧 (ROS) 产生中发挥重要作用。作者此前已表明，Brahma 相关基因 1 (BRG1)（一种染色质重塑蛋白）在多种动物和肝损伤细胞模型中有助于肝脏 ROS 积累。据报道，DNA 损伤诱导转录物 4 (DDIT4) 被确定为 BRG1 的直接转录靶标。DDIT4 过表达克服了 BRG1 缺陷以恢复 ROS 产生，而 DDIT4 敲低表型则复制了 BRG1 缺陷以抑制体外和体内 ROS 产生。从机制上讲，DDIT4 协调 p38-MAPK 信号复合物的组装，以 S-亚硝基化依赖性方式驱动 ROS 产生。分子对接鉴定了几种具有生物活性的 DDIT4 相互作用化合物，包括伊马替尼、尼罗替尼和那格列奈，所有这些化合物都被证实可以通过影响 DDIT4 S-亚硝基化来减弱肝脏 ROS 的产生、抑制 p38-MAPK 信号传导并改善肝损伤。重要的是，在人肝活检标本中检测到 ROS 水平与 BRG1/DDIT4/S-亚硝基化 DDIT4 水平呈正相关。总之，数据揭示了基于转录的信号级联，有助于肝损伤中 ROS 的产生。

更新日期：2021-09-22

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