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Structural basis for RIFlN-mediated activation of LILRB1 in malaria

机译：RIFLN介导的疟疾LILRB1激活的结构基础

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The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur when these parasites replicate in human blood. Despite the risk of immune detection, the parasite delivers proteins that bind to host receptors on the cell surfaces of infected erythrocytes. In the causative parasite of the most deadly form of malaria in humans, Plasmodium falciparum, RIFINs form the largest family of surface proteins displayed by erythrocytes~(1). Some RIFINs can bind to inhibitory immune receptors, and these RIFINs act as targets for unusual antibodies that contain a LAIR1 ectodomain~(2-4)or as ligands for LILRB1~(5). RIFINs stimulate the activation of and signalling by LILRB1~(5), which could potentially lead to the dampening of human immune responses. Here, to understand how RIFINs activate LILRB1-mediated signalling, we determine the structure of a RIFIN bound to LILRB1. We show that this RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics the activation of natural killer (NK) cells by antibody-dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the immunological synapse of NK cells and reduce the activation of NK cells, as measured by the mobilization of perforin. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress the function of NK cells.
机译：导致疟疾的疟原虫物种是迫使细胞内寄生虫，当这些寄生虫在人体血液中复制时，会发生疾病症状。尽管存在免疫检测的风险，但寄生虫递送蛋白质，其在感染的红细胞的细胞表面上结合宿主受体。在人类中最致命的疟疾形式的致病寄生虫中，疟原虫疟原虫，束束形成红细胞显示最大的表面蛋白质〜（1）。一些rifins可以与抑制性免疫受体结合，并且这些步骤作为含有LiLRB1〜（5）的含有褐煤〜（2-4）或配体的异常抗体的靶标。利雷林斯刺激LILRB1〜（5）的激活和信号传导，这可能导致人类免疫反应的抑制。这里，了解如何激活LIFRB1介导的信号传导，我们确定与LILRB1结合的利率的结构。我们表明，这一rifin模仿了LiLRB1，MHC I类，其LILRB1结合模式的自然活化配体。 RIFIN中的单一突变破坏了复合物，阻断了所有测试的束的LILRB1结合并在报告测定中取消了信号传导。在支持的脂质双层系统中，通过抗体依赖性细胞介导的细胞毒性模仿自然杀伤剂（NK）细胞的激活，将RIFIN和MHC募集到NK细胞的免疫突触并降低了测量的NK细胞的激活通过动员穿孔素。因此，LILRB1结合利芬模拟了LILRB1天然配体的结合模式，抑制了NK细胞的功能。

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  • 来源
    《Nature》 |2020年第7833期|309-312|共4页
  • 作者

    Thomas E Harrison; Alexander M Mørch; James H Felce; Akihito Sakoguchi; Adam J Reid; Hisashi Arase; Michael L Dustin; Matthew K Higgins;

  • 作者单位

    Department of Biochemistry University of Oxford;

    Department of Biochemistry University of Oxford|Kennedy Institute of Rheumatology University of Oxford;

    Kennedy Institute of Rheumatology University of Oxford;

    Department of Immunochemistry Research Institute for Microbial Diseases Osaka University|Laboratory of Immunochemistry WPI Immunology Frontier Research Center Osaka University;

    Parasite Genomics Wellcome Sanger Institute;

    Department of Immunochemistry Research Institute for Microbial Diseases Osaka University|Laboratory of Immunochemistry WPI Immunology Frontier Research Center Osaka University;

    Kennedy Institute of Rheumatology University of Oxford;

    Department of Biochemistry University of Oxford;

  • 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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