Helicobacter pylori CagA Interacts with SHP-1 to Suppress the Immune Response by Targeting TRAF6 for K63-Linked Ubiquitination
Helicobacter pylori CagA Interacts with SHP-1 to Suppress the Immune Response by Targeting TRAF6 for K63-Linked Ubiquitination
复制标题
幽门螺杆菌 CagA 与 SHP-1 相互作用，通过靶向 TRAF6 进行 K63 连锁泛素化来抑制免疫反应
DOI：
10.4049/jimmunol.2000234
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发表时间：
2021-03-15
影响因子：
4.4
通讯作者：
Yan, Dapeng
中科院分区：
文献类型：
--
作者：
He, Huan;Liu, Jing;Yan, Dapeng
关键点CagA在体外和体内抑制促炎细胞因子的表达。CagA与SHP-1互动，促进了SHP-1向TRAF 6的招募。CagA与SHP-1相互作用以抑制TRAF 6的K63连接的多聚泛素化。幽门螺杆菌是胃癌的主要致病菌。CagA是H. pylori，但其对免疫反应的影响尚不清楚。在这项研究中，野生型C57 BL/6小鼠和Ptpn 6 me-v/me-v小鼠被随机分配用于感染H.幽门。我们证明CagA抑制H.幽门刺激的促炎细胞因子在体内的表达。此外，我们用H.幽门螺杆菌。结果表明，CagA通过抑制MAPKs和NF-κB通路的活化，抑制了促炎细胞因子的表达。从机制上讲，我们发现CagA与宿主细胞酪氨酸磷酸酶SHP-1相互作用，促进SHP-1向TRAF 6的募集，并抑制TRAF 6的K63连接的泛素化，从而阻碍下游信号的传递。总之，这些发现揭示了CagA在先天性抗菌免疫应答中负调控TRAF 6翻译后修饰的一种先前未知的机制，并为治疗微生物感染的新疗法提供了分子基础。
Key Points CagA suppressed expression of proinflammatory cytokines in vitro and in vivo. CagA interacted with SHP-1 which facilitated the recruitment of SHP-1 to TRAF6. CagA interacts with SHP-1 to inhibit the K63-linked polyubiquitination of TRAF6. Helicobacter pylori is the major etiological agent for most gastric cancer. CagA has been reported to be an important virulence factor of H. pylori, but its effect on the immune response is not yet clear. In this study, wild-type C57BL/6 mice and Ptpn6me-v/me-v mice were randomly assigned for infection with H. pylori. We demonstrated that CagA suppressed H. pylori–stimulated expression of proinflammatory cytokines in vivo. Besides, we infected mouse peritoneal macrophages RAW264.7 and AGS with H. pylori. 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.