小柯机器人

同济大学医学院戈宝学和上海科技大学饶子和研究组合作，揭示了宿主介导的分枝杆菌蛋白泛素化抑制免疫。2020年1月15日，《自然》在线发表了这项成果。

他们报道宿主E3泛素连接酶ANAPC2（后期促进复合物/环体的核心亚基）与分枝杆菌蛋白Rv0222相互作用，并促进11位赖氨酸连接的泛素链对Rv0222的76位赖氨酸的连接，从而抑制促炎细胞因子的表达。特异性的短发夹RNA对ANAPC2的抑制作用抵消了Rv0222对促炎反应的抑制作用。此外，Rv0222上泛素化位点的突变会削弱Rv0222对促炎细胞因子的抑制作用，并降低小鼠感染期间的毒力。从机理上讲，ANAPC2对Rv0222的11位赖氨酸连接的泛素化促进了蛋白酪氨酸磷酸酶SHP1募集到衔接蛋白TRAF6上，从而阻止了63位赖氨酸的连接泛素化和TRAF6的激活。他们的发现确定了结核分枝杆菌用来抑制宿主免疫力的一种以前未被认识的机制，并提供了与开发针对结核分枝杆菌的有效免疫调节剂相关的见解。

研究人员表示，结核分枝杆菌是一种细胞内病原体，它使用多种策略来干扰宿主免疫分子的信号传导功能。许多其他细菌病原体利用宿主泛素化系统促进发病机理，但是该系统是否调节结核分枝杆菌蛋白的泛素化尚不清楚。

附：英文原文

Title: Host-mediated ubiquitination of a mycobacterial protein suppresses immunity

Author: Lin Wang, Juehui Wu, Jun Li, Hua Yang, Tianqi Tang, Haijiao Liang, Mianyong Zuo, Jie Wang, Haipeng Liu, Feng Liu, Jianxia Chen, Zhonghua Liu, Yang Wang, Cheng Peng, Xiangyang Wu, Ruijuan Zheng, Xiaochen Huang, Yajun Ran, Zihe Rao, Baoxue Ge

Issue&Volume: 2020-01-15

Abstract: Mycobacterium tuberculosis is 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 pathogenesis1,2, but whether this same system modulates the ubiquitination of M. tuberculosis proteins 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 that M. tuberculosis uses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

DOI: 10.1038/s41586-019-1915-7

Source: https://www.nature.com/articles/s41586-019-1915-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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