Shanghai Public Health Clinical Center and Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Shanghai Public Health Clinical Center and Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
J Immunol. 2021 Mar 15;206(6):1161-1170. doi: 10.4049/jimmunol.2000234. Epub 2021 Feb 10.
is the major etiological agent for most gastric cancer. CagA has been reported to be an important virulence factor of , but its effect on the immune response is not yet clear. In this study, wild-type C57BL/6 mice and Ptpn6 mice were randomly assigned for infection with We demonstrated that CagA suppressed -stimulated expression of proinflammatory cytokines in vivo. Besides, we infected mouse peritoneal macrophages RAW264.7 and AGS with Our results showed that CagA suppressed expression of proinflammatory cytokines through inhibiting the MAPKs and NF-κB pathways activation in vitro. Mechanistically, we found that CagA interacted with the host cellular tyrosine phosphatase SHP-1, which facilitated the recruitment of SHP-1 to TRAF6 and inhibited the K63-linked ubiquitination of TRAF6, which obstructed the transmission of signal downstream. Taken together, these findings reveal a previously unknown mechanism by which CagA negatively regulates the posttranslational modification of TRAF6 in innate antibacterial immune response and provide molecular basis for new therapeutics to treat microbial infection.
是大多数胃癌的主要病因。CagA 已被报道为 的重要毒力因子，但它对免疫反应的影响尚不清楚。在这项研究中，我们将野生型 C57BL/6 小鼠和 Ptpn6 小鼠随机分配进行 感染。我们证明 CagA 在体内抑制了 - 刺激的促炎细胞因子表达。此外，我们用 感染小鼠腹腔巨噬细胞 RAW264.7 和 AGS。我们的结果表明，CagA 通过抑制 MAPKs 和 NF-κB 途径的激活来抑制体外促炎细胞因子的表达。在机制上，我们发现 CagA 与宿主细胞酪氨酸磷酸酶 SHP-1 相互作用，这促进了 SHP-1 向 TRAF6 的募集，并抑制了 TRAF6 的 K63 连接泛素化，从而阻碍了下游信号的传递。总之，这些发现揭示了 CagA 在先天抗菌免疫反应中负调控 TRAF6 的翻译后修饰的一个先前未知的机制，并为治疗微生物感染的新疗法提供了分子基础。
