F-box and WD repeat domain-containing protein 7 (FBW7) has been documented to be implicated in nuclear factor κB (NF-κB) signaling and inflammation, but its role in the pathogenesis of inflammatory bowel disease (IBD) remains unknown. FBW7 was increased both in colon tissues from IBD patients and trinitrobenzene sulphonic acid (TNBS)-induced colitis mice. Immunoprecipitation assay identified that FBW7 as a novel inhibitor of κBα (IκBα)-binding partner. FBW7 upregulation promoted IκBα ubiquitin-dependent degradation, NF-κB activation, and subsequent intestinal inflammation in intestinal epithelial cells, whereas inhibition of FBW7 produced the opposite effects. Computational analysis revealed that microRNA-129 (miR-129) directly targets at 3′ UTR of FBW7. The miR-129-suppressed proteasome pathway mediated the degradation of IκBα by negatively regulating FBW7. The in vivo study demonstrated that upregulation of miR-129 ameliorated intestinal inflammation in TNBS-induced colitis mice through inhibition of the NF-κB signaling pathway. In conclusion, FBW7 is a novel E3 ubiquitin ligase for IκBα and thereby leads to NF-κB activation and inflammation. miR-129 negatively regulates FBW7 expression, resulting in secondary inhibition of the NF-κB pathway and amelioration of intestinal inflammation. Our findings provide new insight into the development of therapeutic strategies for the treatment of IBD.

F-box 和含 WD 重复结构域的蛋白 7 (FBW7) 已被证明与核因子 κB (NF-κB) 信号传导和炎症有关，但其在炎症性肠病 (IBD) 发病机制中的作用仍不清楚。 IBD 患者和三硝基苯磺酸 (TNBS) 诱导的结肠炎小鼠的结肠组织中 FBW7 均增加。免疫沉淀测定确定 FBW7 是 κBα (IκBα) 结合伴侣的新型抑制剂。 FBW7 上调促进 IκBα 泛素依赖性降解、NF-κB 激活以及随后肠上皮细胞中的肠道炎症，而抑制 FBW7 则产生相反的效果。计算分析表明 microRNA-129 (miR-129) 直接靶向 FBW7 的 3' UTR。 miR-129 抑制的蛋白酶体途径通过负调节 FBW7 介导 IκBα 的降解。体内研究表明，miR-129 的上调可通过抑制 NF-κB 信号通路改善 TNBS 诱导的结肠炎小鼠的肠道炎症。总之，FBW7 是 IκBα 的新型 E3 泛素连接酶，从而导致 NF-κB 激活和炎症。 miR-129 负向调节 FBW7 表达，导致 NF-κB 通路的二次抑制并改善肠道炎症。我们的研究结果为 IBD 治疗策略的开发提供了新的见解。