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RIFIN介导LILRB1激活的结构基础获解析
2020-07-13 22:41

英国牛津大学Matthew K. Higgins研究组解析出RIFIN介导LILRB1激活的结构基础。相关论文于2020年7月10日在线发表在《自然》杂志上。

据研究人员介绍,引起疟疾的疟原虫是专性的细胞内寄生虫,在人类血液中复制时会出现疾病症状。尽管有被免疫系统识别的风险,但该寄生虫仍递送了能够与宿主受体结合,进而感染的红细胞表面的蛋白质。在最致命的人类疟疾(恶性疟原虫)的病原体中,RIFIN构成了最大的红细胞表面蛋白家族。一些RIFIN可以结合抑制性免疫受体,充当包含LAIR1胞外域的抗体靶标,或充当LILRB1的配体。RIFIN刺激LILRB1的激活和信号传导,从而有可能抑制人类的免疫反应。
 
为了理解此过程,研究人员确定了结合LILRB1的RIFIN结构。研究人员表明,RIFIN模拟LILRB1的天然活化配体MHC I。单个RIFIN突变会破坏复合物,阻断所有已测试RIFIN与LILRB1的结合,并消除报告基因分析中的信号。在脂质双层系统中(这一系统通过抗体依赖性细胞介导的细胞毒性模拟NK细胞的活化),RIFIN和MHC均被募集到NK细胞的免疫突触中,并通过穿孔素动员来降低细胞的活化。因此,结合LILRB1的RIFIN模拟了LILRB1天然配体的结合模式并抑制NK细胞功能。
 
附:英文原文

Title: Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Author: Thomas E. Harrison, Alexander M. Mrch, James H. Felce, Akihito Sakoguchi, Adam J. Reid, Hisashi Arase, Michael L. Dustin, Matthew K. Higgins

Issue&Volume: 2020-07-10

Abstract: The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur as they replicate within human blood. Despite risking immune detection, the parasite delivers proteins that bind host receptors to infected erythrocyte surfaces. In the causative agent of the most deadly human malaria, Plasmodium falciparum, RIFINs form the largest erythrocyte surface protein family1. Some RIFINs can bind inhibitory immune receptors, acting as targets for unusual antibodies containing a LAIR1 ectodomain2–4, or as ligands for LILRB15. RIFINs stimulate LILRB1 activation and signalling5, thereby potentially dampening human immune responses. To understand this process, we determined a structure of a RIFIN bound to LILRB1. We show that the RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single RIFIN mutation disrupts the complex, blocks LILRB1 binding by all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics NK cell activation by antibody-dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the NK cell immunological synapse and reduce cell activation, as measured by perforin mobilisation. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress NK cell function.

DOI: 10.1038/s41586-020-2530-3

Source: https://www.nature.com/articles/s41586-020-2530-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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