Nuclear factor κB (NF-κB)–mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium– or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

核因子 κB (NF-κB) 介导的信号通路在炎症过程、先天性和适应性免疫反应的调节中起着至关重要的作用。炎症反应的过度激活导致宿主细胞死亡、组织损伤和自身炎症性疾病，例如败血症和炎症性肠病。然而，如何精确控制这些过程仍然知之甚少。在这项研究中，我们证明了锚蛋白重复序列​​和含有 1 (ASB1) 的细胞因子信号盒抑制因子通过增强 TAB2 及其下游信号通路（包括 NF-κB 和丝裂原活化蛋白）的稳定性来参与炎症反应的正向调节。激酶途径。从机制上讲，与诱导泛素化介导的靶蛋白降解的 ASB 家族的其他成员不同，ASB1 与 TAB2 结合以抑制 K48 连接的多泛素化，从而在细胞因子和脂多糖 (LPS) 的刺激下促进 TAB2 的稳定性，这表明 ASB1 在进一步稳定靶蛋白而不是诱导其降解方面发挥了非常规的作用。的不足Asb1保护小鼠免受鼠伤寒沙门氏菌或 LPS 诱导的感染性休克，并提高小鼠的存活率。此外，缺乏 Asb1的小鼠表现出由葡聚糖硫酸钠诱导的不太严重的结肠炎和肠道炎症。鉴于 ASB 蛋白在炎症信号通路中的关键作用，我们的研究为病原体感染和炎症性疾病中的免疫调节提供了见解，并具有治疗意义。