E3 泛素连接酶 (E3) 通过介导泛素化在调节炎症反应中发挥着至关重要的作用。先前的研究表明，锚蛋白重复序列​​和含有 SOCS 盒的蛋白 3 (ASB3) 参与与癌症相关的免疫调节功能。然而，ASB3 对炎症性肠病 (IBD) 中微生物群和炎症反应的动态相互作用的影响尚不清楚。在这里，我们系统地鉴定了 E3 连接酶 ASB3 作为 IBD 发生和进展的促进调节剂。我们观察到 ASB3 在 IBD 患者的病变中表现出显着的上调。 ASB3-/- 小鼠对葡聚糖硫酸钠诱导的结肠炎具有抵抗力。与 WT 小鼠相比，ASB3-/- 小鼠结肠组织中 IκBα 磷酸化水平和促炎因子 IL-1β、IL-6 和 TNF-α 的产生减少。这种结肠炎耐药表型在食粪微生物转移后受到抑制，并在联合抗生素去除肠道共生微生物组后逆转。从机制上讲，ASB3 特异性催化肠上皮细胞中 TRAF6 的 K48 连接的多聚泛素化。相比之下，在 ASB3 缺陷的类器官中，TRAF6 蛋白的完整性受到保护，从而减缓肠道炎症的发生。 ASB3 与结肠炎微生物群失调相关，并通过破坏 TRAF6 稳定性促进促炎因子的产生。限制肠上皮细胞中 ASB3 蛋白水平的策略可能有助于治疗结肠炎。泛素化是控制蛋白质稳定性的关键过程。我们确定了结肠炎症期间肠上皮细胞中 ASB3 对 TRAF6 的泛素化。炎症性肠病患者在病灶部位表现出 ASB3 表达上调，支持 TRAF6 的降解，从而促进 TLR-Myd88/TRIF 独立的 NF-κB 异常激活和肠道微生物群失衡。肠上皮细胞中持续的炎症信号传导和 ASB3 介导的保护性益生菌免疫反应失调共同导致炎症性肠病的恶化。这些发现提供了对炎症性肠病发病机制的见解，并提出了 ASB3 增加结肠炎风险的新机制。我们的结果表明，未来抑制肠上皮细胞中的 ASB3 可能是一种新的临床策略。

E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here, we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. We observed that ASB3 exhibited significant upregulation in the lesions of patients with IBD. ASB3-/- mice are resistant to dextran sodium sulfate-induced colitis. IκBα phosphorylation levels and production of proinflammatory factors IL-1β, IL-6, and TNF-α were reduced in the colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotics removed the gut commensal microbiome. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in intestinal epithelial cells. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors' production by disrupting TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis.Ubiquitination is a key process that controls protein stability. We determined the ubiquitination of TRAF6 by ASB3 in intestinal epithelial cells during colonic inflammation. Inflammatory bowel disease patients exhibit upregulated ASB3 expression at focal sites, supporting the involvement of degradation of TRAF6, which promotes TLR-Myd88/TRIF-independent NF-κB aberrant activation and intestinal microbiota imbalance. Sustained inflammatory signaling in intestinal epithelial cells and dysregulated protective probiotic immune responses mediated by ASB3 collectively contribute to the exacerbation of inflammatory bowel disease. These findings provide insights into the pathogenesis of inflammatory bowel disease and suggest a novel mechanism by which ASB3 increases the risk of colitis. Our results suggest that future inhibition of ASB3 in intestinal epithelial cells may be a novel clinical strategy.