An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis
An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis
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ASB 家族蛋白在微生物感染和结肠炎期间 NF-κ B 激活和炎症反应中的非常规作用
DOI：
10.1073/pnas.2015416118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Guo, Deyin
中科院分区：
文献类型：
--
作者：
Hou, Panpan;Jia, Penghui;Guo, Deyin
核因子κ B （nf - κ B）介导的信号通路在炎症过程、先天和适应性免疫反应的调控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，如败血症和炎症性肠病。然而，这些过程是如何被精确控制的，人们仍然知之甚少。在本研究中，我们发现含有1的细胞因子信号传导盒的锚定蛋白重复和抑制因子（ASB1）通过增强TAB2及其下游信号通路，包括NF-kappa B和丝裂原活化蛋白激酶通路的稳定性，参与了炎症反应的正向调节。机制上，与ASB家族其他成员诱导泛素化介导的靶蛋白降解不同，ASB1与TAB2结合抑制k48相关的多泛素化，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方面发挥非规范作用，而不是诱导其降解。缺乏Asb1可以保护小鼠免受鼠伤寒沙门菌或脂多糖诱导的脓毒性休克，并提高小鼠的存活率。此外，葡聚糖硫酸钠诱导的asb1缺陷小鼠结肠炎和肠道炎症较轻。鉴于ASB蛋白在炎症信号通路中的重要作用，我们的研究为病原体感染和炎症疾病的免疫调节提供了新的见解，具有治疗意义。
Nuclear factor kappa B (NF-kappa B)-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-kappa B 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.