Li Zilong, Zhao Qianwen, Lu Yunjie, Zhang Yangxi, Li Luyang, Li Min, Chen Xuemin, Sun Donglin, Duan Yunfei, Xu Yong
Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, China.
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, 211166, China.
Adv Sci (Weinh). 2021 Sep;8(18):e2101957. doi: 10.1002/advs.202101957. Epub 2021 Jul 26.
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.
丝裂原活化蛋白激酶（MAPK）信号传导在活性氧（ROS）生成中起重要作用。作者先前已表明，染色质重塑蛋白布拉马相关基因1（BRG1）在多种肝损伤动物和细胞模型中促进肝脏ROS积累。在此报告，DNA损伤诱导转录物4（DDIT4）被鉴定为BRG1的直接转录靶点。DDIT4过表达克服了BRG1缺陷以恢复ROS生成，而DDIT4敲低在体外和体内抑制ROS生成方面模拟了BRG1缺陷。机制上，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生成。分子对接鉴定出几种具有生物活性的DDIT4相互作用化合物，包括伊马替尼、尼洛替尼和那格列奈，所有这些化合物均被证实可通过影响DDIT4的S-亚硝基化来减轻肝脏ROS生成、抑制p38-MAPK信号传导并改善肝损伤。重要的是，在人类肝活检标本中检测到ROS水平与BRG1/DDIT4/S-亚硝基化DDIT4水平之间呈正相关。总之，这些数据揭示了一种基于转录的信号级联反应，其在肝损伤中促进ROS生成。
