Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia-Reperfusion Injury in Mice.
Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia-Reperfusion Injury in Mice.
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综合组学揭示 Tollip 作为小鼠肝缺血再灌注损伤的调节剂和治疗靶点。
DOI：
10.1002/hep.30705
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发表时间：
2019
期刊：
影响因子：
13.5
通讯作者：
Li Hongliang
中科院分区：
文献类型：
--
作者：
Yan Zhen Zhen;Huang Yong Ping;Wang Xin;Wang Hai Ping;Ren Fei;Tian Rui Feng;Cheng Xu;Cai Jie;Zhang Yan;Zhu Xue Yong;She Zhi Gang;Zhang Xiao Jing;Huang Zan;Li Hongliang
肝脏缺血再灌注（IR）损伤是肝脏切除或移植后肝功能障碍和衰竭的主要原因，缺乏有效的治疗策略。在这里，我们应用了系统的蛋白质组学分析，以确定IR诱导的肝损伤的主要贡献者和这种疾病的有希望的治疗靶点。基于无偏蛋白质组学分析，我们发现toll相互作用蛋白（Tollip）表达与肝脏IR过程密切相关。RNA测序分析和表型检测显示Tollipdeficiency可明显减轻肝脏IR损伤。从机制上讲，Tollip与凋亡信号调节激酶1（ASK 1）相互作用，促进肿瘤坏死因子受体相关因子6（TRAF 6）向ASK 1的募集，导致ASK 1 N末端二聚化增强，随后激活下游丝裂原活化蛋白激酶（MAPK）信号传导。结论：Tollip通过促进ASK 1 N末端二聚化和c-Jun N末端激酶/p38信号通路的激活，调节肝脏IR损伤。抑制Tollip或抑制其与ASK 1的相互作用可能是治疗肝脏IR损伤的有希望的策略。
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 byTollipdeficiency bothin vivoand 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.