Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways
Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways
复制标题
三联基序 8 缺陷通过 TAK1 依赖性信号通路缓解肝脏缺血/再灌注损伤
DOI：
10.7150/ijbs.33323
复制
发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Zou Jilin
中科院分区：
文献类型：
--
作者：
Qiu Tao;Wang Tianyu;Zou Jilin
三方基序(Trip-te Motif，TRIM)8是一种E3泛素连接酶，与多种底物相互作用并泛化，与先天免疫密切相关。然而，Trim8在肝脏缺血/再灌注(I/R)损伤中的作用尚不清楚。本研究旨在探讨TRIM8在肝脏I/R损伤中的作用。采用Trim8基因敲除小鼠和原代肝细胞建立肝脏I/R模型。通过病理学和分子生物学方法分析TRIM8对肝脏I/R损伤的影响。结果表明，小鼠肝脏I/R损伤后，Trim8在肝脏中的表达明显上调。Trim8基因敲除可减轻I/R引起的肝细胞损伤，抑制Trim8的表达，减轻肝脏炎症反应，抑制体内和体外的细胞凋亡。从机制上讲，我们的研究表明，Trim8缺乏可能通过抑制转化生长因子-β激活激酶1(TAK1)-p38/JNK信号通路的激活而产生肝脏保护作用。在肝脏I/R损伤中，由于TAK1的激活取消了Trim8的功能，因此在肝脏I/R损伤中需要TAK1来发挥Trim8的功能。总之，我们的研究表明，Trim8缺乏通过抑制TAK1依赖的信号通路的激活而在肝脏I/R损伤中起到保护作用。
Tripartite motif (Trim) 8 is an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is closely involved in innate immunity. However, the function of Trim8 in hepatic ischaemia/reperfusion (I/R) injury remains largely unknown. The aim of this study is to explore the role of Trim8 in hepatic I/R injury. Trim8 gene knockout mice and primary hepatocytes were used to construct hepatic I/R models. The effect of Trim8 on hepatic I/R injury was analysed via pathological and molecular analyses. The results indicated that Trim8 was significantly upregulated in liver of mice subjected to hepatic I/R injury. Trim8 knockout relieved hepatocyte injury triggered by I/R. Silencing of Trim8 expression alleviated hepatic inflammation responses and inhibited apoptosis in vitro and in vivo. Mechanistically, our study suggests that Trim8 deficiency may elicit hepatic protective effects by inhibiting the activation of transforming growth factor beta-activated kinase 1 (TAK1)-p38/JNK signalling pathways. TAK1 was required for Trim8 function in hepatic I/R injury as TAK1 activation abolished Trim8 function in vitro. In conclusion, our study demonstrates that Trim8 deficiency plays a protective role in hepatic I/R injury by inhibiting the activation of TAK1-dependent signalling pathways.