信号转导
糖基转移酶
ASK1
再灌注损伤
p38丝裂原活化蛋白激酶
生物
肝移植
癌症研究
蛋白激酶A
细胞生物学
药理学
缺血
激酶
医学
肝损伤
化学
细胞凋亡
酶
移植
生物化学
内科学
丝裂原活化蛋白激酶激酶
作者
Jiangqiao Zhou,Lijia Guo,Tengfei Ma,Tao Qiu,Sichen Wang,Tian Shen,Li Zhang,Fengjiao Hu,Wei Li,Zhen Liu,Yufeng Hu,Tianyu Wang,Chenyang Kong,Juan Yang,Junjie Zhou,Hongliang Li
出处
期刊:Hepatology
[Wiley]
日期:2021-12-19
卷期号:75 (6): 1446-1460
被引量:19
摘要
Ischemia-reperfusion (I/R) injury is an inevitable complication of liver transplantation (LT) and compromises its prognosis. Glycosyltransferases have been recognized as promising targets for disease therapy, but their roles remain open for study in hepatic I/R (HIR) injury. Here, we aim to demonstrate the exact function and molecular mechanism of a glycosyltransferase, N-acetylgalactosaminyltransferase-4 (GALNT4), in HIR injury.By an RNA-sequencing data-based correlation analysis, we found a close correlation between GALNT4 expression and HIR-related molecular events in a murine model. mRNA and protein expression of GALNT4 were markedly up-regulated upon reperfusion surgery in both clinical samples from subjects who underwent LT and in a mouse model. We found that GALNT4 deficiency significantly exacerbated I/R-induced liver damage, inflammation, and cell death, whereas GALNT4 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration clarified that GALNT4 directly binds to apoptosis signal-regulating kinase 1 (ASK1) to inhibit its N-terminal dimerization and subsequent phosphorylation, leading to a robust inactivation of downstream c-Jun N-terminal kinase (JNK)/p38 and NF-κB signaling. Intriguingly, the inhibitory capacity of GALNT4 on ASK1 activation is independent of its glycosyltransferase activity.GALNT4 represents a promising therapeutic target for liver I/R injury and improves liver surgery prognosis by inactivating the ASK1-JNK/p38 signaling pathway.
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