Host-mediated ubiquitination of a mycobacterial protein suppresses immunity
Host-mediated ubiquitination of a mycobacterial protein suppresses immunity
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宿主介导的分枝杆菌蛋白泛素化抑制免疫
DOI：
10.1038/s41586-019-1915-7
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发表时间：
2020-01-15
期刊：
影响因子：
64.8
通讯作者：
Ge, Baoxue
中科院分区：
文献类型：
--
作者：
Wang, Lin;Wu, Juehui;Ge, Baoxue
结核分枝杆菌是一种细胞内病原体，它使用几种策略来干扰宿主免疫分子的信号功能。许多其他细菌病原体利用宿主的泛素化系统来促进致病，但是否同一系统调节M. tuberculosisproteins是未知的。在这里，我们报告的主机E3泛素连接酶ANAPC 2-一个核心亚基的后期促进复合物/cyclosome-interacting与分枝杆菌蛋白Rv 0222和促进附件的赖氨酸-11-连接的泛素链的Rv 0222的赖氨酸76，以抑制促炎细胞因子的表达。特异性短发夹RNA对ANAPC 2的抑制消除了Rv 0222对促炎反应的抑制作用。此外，Rv 0222上的泛素化位点的突变削弱了Rv 0222对促炎细胞因子的抑制，并降低了小鼠感染期间的毒力。从机制上讲，ANAPC 2对Rv 0222的赖氨酸-11-连接的泛素化促进了蛋白酪氨酸磷酸酶SHP 1向衔接蛋白TRAF 6的募集，阻止了TRAF 6的赖氨酸-63-连接的泛素化和激活。我们的研究结果确定了一个以前未被认识的机制，M。结核病抑制宿主免疫，并提供相关的见解，有效的免疫调节剂，靶向M的发展。结核
Mycobacterium tuberculosisis an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis,, but whether this same system modulates the ubiquitination ofM. tuberculosisproteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2—a core subunit of the anaphase-promoting complex/cyclosome—interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific short hairpin RNA abolishes the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impairs the inhibition of proinflammatory cytokines by Rv0222 and reduces virulence during infection in mice. Mechanistically, lysine-11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing the lysine-63-linked ubiquitination and activation of TRAF6. Our findings identify a previously unrecognized mechanism thatM. tuberculosisuses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that targetM. tuberculosis.