Tripartite Motif-Containing 27 Attenuates Liver Ischemia/Reperfusion Injury by Suppressing Transforming Growth Factor β-Activated Kinase 1 (TAK1) by TAK1 Binding Protein 2/3 Degradation.
Tripartite Motif-Containing 27 Attenuates Liver Ischemia/Reperfusion Injury by Suppressing Transforming Growth Factor β-Activated Kinase 1 (TAK1) by TAK1 Binding Protein 2/3 Degradation.
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三联基序 — 含有 27 通过 TAB2/3 降解抑制 TAK1，从而减轻肝脏缺血/再灌注损伤
DOI：
10.1002/hep.31295
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Zhang SJ
中科院分区：
文献类型：
--
作者：
Chen SY;Zhang HP;Li J;Shi JH;Tang HW;Zhang Y;Zhang JK;Wen PH;Wang ZH;Shi XY;He YT;Hu BW;Yang H;Guo WZ;Zhang SJ
肝缺血再灌注(I/R)损伤是肝移植(LT)中器官功能障碍的常见原因，主要涉及炎症反应和细胞凋亡。作为多种细胞炎症和凋亡的重要介质，含三方基序(TRIM)27在肝脏I/R损伤中的作用仍值得研究。本研究系统地探讨了TRIM27/转化生长因子β激活蛋白1/c-jun氨基末端激酶/p38信号转导通路在肝I/R损伤中的作用。在肝移植患者、肝I/R手术小鼠和缺氧/复氧(H/R)处理的肝细胞中，TRIM27的表达显著下调。随后，使用全局Trim27基因敲除小鼠(Trim27-KO小鼠)和肝细胞特异性Trim27转基因小鼠(Trim27-HTG小鼠)，TRIM27具有改善肝脏损伤、减少炎症反应和防止细胞凋亡的功能。在平行的体外研究中，激活TRIM27也可以防止H/R诱导的肝细胞炎症和凋亡。在机制上，TRIM27与关键成分TAK1和TAK1结合蛋白2/3(TAB2/3)发生结构性相互作用，促进TAB2/3的降解，导致TAK1失活，进而抑制下游的JNK/p38信号传导。TRIM27是肝脏I/R损伤的关键调节因子，通过介导TAB2/3的降解和抑制下游的TAK1-JNK/p38信号通路而发挥作用。TRIM27可能是一种很有前途的方法来保护移植受体的肝脏免受I/R介导的肝细胞损伤。
Hepatic ischemia‐reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif‐containing (TRIM) 27 in hepatic I/R injury remains worthy of study. This study systemically evaluated the putative role of TRIM27/transforming growth factor β–activated kinase 1 (TAK1)/JNK (c‐Jun N‐terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down‐regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27‐KO mice) and hepatocyte‐specific Trim27 transgenic mice (Trim27‐HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R‐induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling. TRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1‐JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R‐mediated hepatocellular damage in transplant recipients.
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