ASK1
MAPK/ERK通路
激酶
蛋白激酶A
癌症研究
医学
缺血
细胞生物学
再灌注损伤
信号转导
生物
肝损伤
调节器
丝裂原活化蛋白激酶激酶
药理学
内科学
生物化学
基因
作者
Zhenzhen Yan,Yaji Huang,Xin Wang,Haiping Wang,Fei Ren,Ruifeng Tian,Xu Cheng,Jie Cai,Yan Zhang,Xueyong Zhu,Zhi‐Gang She,Xiaojing Zhang,Zan Huang,Hongliang Li
出处
期刊:Hepatology
[Wiley]
日期:2019-06-22
卷期号:70 (5): 1750-1769
被引量:44
摘要
Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.
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