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Host-mediated ubiquitination of a mycobacterial protein suppresses immunity

机译：宿主介导的分枝杆菌蛋白泛素抑制免疫力

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摘要

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 pathogenesis(1,2), 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.
机译：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。许多其他细菌性病原体利用宿主泛素化系统促进发病机理（1,2），但是该系统是否能调节结核分枝杆菌蛋白的泛素化尚不清楚。在这里，我们报道宿主E3泛素连接酶ANAPC2-a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，并促进赖氨酸11连接的泛素链对Rv0222的赖氨酸76的附着，以抑制促炎细胞因子的表达。特定的短发夹RNA对ANAPC2的抑制作用消除了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，并降低小鼠感染过程中的毒力。从机理上讲，ANAPC2对Rv0222的赖氨酸11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，从而阻止了赖氨酸63的连接泛素化和TRAF6的激活。我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有关的见解。

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  • 来源
    《Nature》 |2020年第7792期|682-688|共7页
  • 作者

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

  • 作者单位

    Tongji Univ Sch Med Shanghai Pulm Hosp Shanghai Key Lab TB Shanghai Peoples R China;

    Tongji Univ Sch Med Shanghai Pulm Hosp Shanghai Key Lab TB Shanghai Peoples R China|Tongji Univ Dept Microbiol & Immunol Sch Med Shanghai Peoples R China;

    ShanghaiTech Univ Shanghai Inst Adv Immunochem Studies Shanghai Peoples R China|ShanghaiTech Univ Sch Life Sci & Technol Shanghai Peoples R China;

    Tongji Univ Dept Microbiol & Immunol Sch Med Shanghai Peoples R China;

    Tongji Univ Sch Med Shanghai Pulm Hosp Shanghai Key Lab TB Shanghai Peoples R China|Tongji Univ Shanghai Pulm Hosp Clin Translat Res Ctr Sch Med Shanghai Peoples R China;

    ShanghaiTech Univ Shanghai Inst Adv Immunochem Studies Shanghai Peoples R China|ShanghaiTech Univ Sch Life Sci & Technol Shanghai Peoples R China|Tsinghua Univ Struct Biol Lab Beijing Peoples R China|Nankai Univ Coll Life Sci State Key Lab Med Chem Biol Tianjin Peoples R China|Nankai Univ Coll Pharm Tianjin Peoples R China|Chinese Acad Sci Natl Lab Biomacromol Ctr Excellence Biomacromol Inst Biophys Beijing Peoples R China;

    Tongji Univ Sch Med Shanghai Pulm Hosp Shanghai Key Lab TB Shanghai Peoples R China|Tongji Univ Dept Microbiol & Immunol Sch Med Shanghai Peoples R China|Tongji Univ Shanghai Pulm Hosp Clin Translat Res Ctr Sch Med Shanghai Peoples R China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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