Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Biochem Biophys Res Commun. 2020 Mar 19;523(4):924-930. doi: 10.1016/j.bbrc.2019.12.114. Epub 2020 Jan 19.
Hepatic ischemia-reperfusion (IR) injury can cause serious liver damage, leading to liver dysfunction after liver surgery, which is associated with NF-κB-mediated inflammation. The K63-linked auto-polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB. Here, we found that OTU domain-containing protein 4 (OTUD4), a deubiquitinating enzyme (DUB), interacts with TRAF6 and decreases the K63 auto-polyubiquitination of TRAF6. In addition, the data showed that NF-κB activation was impaired and inflammatory factor levels were reduced after overexpressing OTUD4 in a hypoxia/reoxygenation (HR) model and a hepatic IR model. Additionally, the liver inflammatory response and tissue damage were ameliorated in mice overexpressing OTUD4.Taken together, these results show that OTUD4 can negatively regulate NF-κB activation by suppressing the K63-linked ubiquitination of TRAF6, thus alleviating hepatic ischemia-reperfusion injury.
肝缺血再灌注（IR）损伤可导致严重的肝损伤，导致肝手术后肝功能障碍，这与 NF-κB 介导的炎症有关。肿瘤坏死因子受体相关因子 6（TRAF6）的 K63 连接的自身泛素化对于 NF-κB 的激活至关重要。在这里，我们发现含有 OTU 结构域的蛋白 4（OTUD4），一种去泛素化酶（DUB），与 TRAF6 相互作用，并降低 TRAF6 的 K63 自身泛素化。此外，数据显示，在缺氧/复氧（HR）模型和肝 IR 模型中过表达 OTUD4 后，NF-κB 激活受损，炎症因子水平降低。此外，在过表达 OTUD4 的小鼠中，肝的炎症反应和组织损伤得到改善。总之，这些结果表明，OTUD4 通过抑制 TRAF6 的 K63 连接泛素化来负调控 NF-κB 激活，从而减轻肝缺血再灌注损伤。
