TRIM31 promotes apoptosis via TAK1-mediated activation of NF-κB signaling in sepsis-induced myocardial dysfunction

Sepsis is a major condition caused by an overwhelming inflammatory response to an infection. Sepsis-induced myocardial dysfunction (SIMD) is a common complication in septic patients and a major predictor of morbidity and mortality. Here, we investigated the role of tripartite motif 31 (TRIM31) protein in sepsis progression in vitro and in vivo. Quantitative real-time PCR and western blot were used to detect the expression levels of relative genes and proteins. Cell proliferation and apoptosis were evaluated to determine cell viability. H&E and IHC staining were performed to examine morphological and pathological changes in mice. ELISA assay was used to detect inflammatory factors. TRIM31 was upregulated in septic patients compared with normal people. TRIM31 depletion reduced LPS-induced apoptosis whereas TRIM31 overexpression-elevated LPS-induced apoptosis. Furthermore, TRIM31 interacted with and ubiquitinated transforming growth factor-β-activated kinase-1 (TAK1), resulting in TAK1 activation and subsequent induction of NF-κB signaling. Of note, Trim31 depletion or blockade by PDTC treatment inhibited LPS-induced apoptosis in vivo. In conclusion, TRIM31 played an important role in SIMD by activating TAK1-mediated NF-κB signaling pathway.

脓毒症（Sepsis）是机体对感染产生过度炎症反应所引发的严重病症。脓毒症相关心肌功能障碍（SIMD）是脓毒症患者的常见并发症，亦是其发病率与死亡率的关键预测因子。本研究分别在体外与体内环境中，探究了三重基序蛋白31（TRIM31）在脓毒症进程中的作用。采用实时定量PCR（quantitative real-time PCR）与蛋白质免疫印迹（Western Blot）检测相关基因与蛋白的表达水平；通过细胞增殖与凋亡实验评估细胞活力；采用苏木精-伊红（H&E）染色与免疫组织化学（IHC）染色检测小鼠的形态与病理变化；利用酶联免疫吸附实验（ELISA）检测炎症因子水平。实验结果显示，与健康人群相比，脓毒症患者体内TRIM31的表达水平上调。敲低TRIM31可减轻脂多糖（LPS）诱导的细胞凋亡，而过表达TRIM31则会加剧LPS诱导的细胞凋亡。进一步研究表明，TRIM31可与转化生长因子-β激活激酶1（TAK1）相互结合并对其进行泛素化修饰，进而激活TAK1并下游激活核因子κB（NF-κB）信号通路。值得注意的是，在体内实验中，敲低Trim31或用PDTC进行通路阻断均可抑制LPS诱导的细胞凋亡。综上，TRIM31通过激活TAK1介导的NF-κB信号通路，在脓毒症相关心肌功能障碍中发挥了重要作用。