KEAP1型
氧化应激
下调和上调
炎症
化学
医学
体内
癌症研究
免疫学
生物
生物化学
基因
转录因子
生物技术
作者
Xiaofeng Sun,Chaorui Guo,Chunyan Huang,Ning Lv,Huili Chen,Haoyan Huang,Yulin Zhao,Shan‐Liang Sun,Dan Zhao,Jingwei Tian,Xijing Chen,Yongjie Zhang
出处
期刊:Redox biology
[Elsevier]
日期:2024-05-01
卷期号:71: 103116-103116
标识
DOI:10.1016/j.redox.2024.103116
摘要
Oxidative stress plays an important role in the pathogenesis of acute lung injury (ALI). As a typical post-translational modification triggered by oxidative stress, protein S-glutathionylation (PSSG) is regulated by redox signaling pathways and plays diverse roles in oxidative stress conditions. In this study, we found that GSTP downregulation exacerbated LPS-induced injury in human lung epithelial cells and in mice ALI models, confirming the protective effect of GSTP against ALI both in vitro and in vivo. Additionally, a positive correlation was observed between total PSSG level and GSTP expression level in cells and mice lung tissues. Further results demonstrated that GSTP inhibited KEAP1-NRF2 interaction by promoting PSSG process of KEAP1. By the integration of protein mass spectrometry, molecular docking, and site-mutation validation assays, we identified C434 in KEAP1 as the key PSSG site catalyzed by GSTP, which promoted the dissociation of KEAP1-NRF2 complex and activated the subsequent anti-oxidant genes. In vivo experiments with AAV-GSTP mice confirmed that GSTP inhibited LPS-induced lung inflammation by promoting PSSG of KEAP1 and activating the NRF2 downstream antioxidant pathways. Collectively, this study revealed the novel regulatory mechanism of GSTP in the anti-inflammatory function of lungs by modulating PSSG of KEAP1 and the subsequent KEAP1/NRF2 pathway. Targeting at manipulation of GSTP level or activity might be a promising therapeutic strategy for oxidative stress-induced ALI progression.
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