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PTEX is an essential nexus for protein export in malaria parasites

机译：PTEX是疟疾寄生虫蛋白质出口的重要纽带

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摘要

During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol. These proteins have a variety of roles that are essential to virulence or parasite growth. There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins. One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX). Although PTEX has been linked to the export of one class of exported proteins, there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) and PEXEL-negative exported proteins (PNEPs). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target.%镰刀形疟原虫感染和重塑宿主的红血球,该过程是要求向细胞溶质内输出数百种蛋白的一个过程。这是一个相当拓扑化的过程,因为疟原虫最初呆在一个被称为"寄生泡"的腔室中。 名为PTEX(被输出的蛋白的镰刀形疟原虫易位子）的一个蛋白复合物过去被认为参与了这一过程,但功能证据是佐证性的和间接的。本期Nafure上的两篇报告采用对比性方法显示, PTEX是疟原虫蛋白向被感染细胞的胞质内的输出所必需的,同时这种输出又是疟原虫的生命周期所必需的。Brendan Elsworth等人生成了PTEX的成分HSP101和PTEX150的条件突变体,发现当PTEX的功能被扰动时,包括主要毒性因子PfEMP1在内的蛋白的输出被大大减少。Josh Beck等人采用一种基于"二氢叶酸还原酶''的创新的"去稳定化域"方法来使 HSP101失活,发现它是所有类别的被输出疟疾蛋白的分泌所需的。
机译：在疟疾的血液阶段，数百种寄生虫编码的蛋白质被输出到将寄生虫与宿主细胞胞质溶胶分开的双膜屏障之外。这些蛋白质具有多种作用，对于毒力或寄生虫的生长至关重要。人们对了解蛋白质的出口方式以及运输不同类别的出口蛋白质是否涉及共同的机制有着浓厚的兴趣。一种潜在的贩运机器是一种蛋白质复合物，称为输出蛋白质的疟原虫转座子（PTEX）。尽管PTEX与一类出口蛋白质的出口相关，但尚无直接证据证明其在蛋白质转运中的作用和范围。在这里，我们显示出，通过生成对于必需的PTEX组件（HSP101或PTEX150）有缺陷的两条寄生线，以及对缺乏非必需成分TRX2的线的分析（参考文献12），大大减少了除出口蛋白外的所有类别的蛋白运输。双层膜屏障包裹了寄生虫。这包括含有PEXEL基序（RxLxE / Q / D）和PEXEL阴性输出蛋白（PNEPs）的蛋白质。此外，在恶性疟原虫中，用于表达在感染的红细胞表面上表达的蛋白质（包括恶性疟原虫中的主要毒力因子PfEMP1）显着减少。 PTEX功能对于血液阶段的生长也是必不可少的，因为即使适度敲除PTEX成分，也对体外和体内寄生虫完成红细胞周期的能力都有很大影响。因此，PTEX作为疟原虫中唯一已知的蛋白质输出联系和必不可少的酶机器，是主要药物靶标。％镰刀形寄生原虫感染和重塑宿主的红血球，该过程是要求向细胞溶质内输出数百种蛋白的一个过程。这是一个相当突变化的过程，因为急性原虫最初呆在一个被称为“寄生泡”的腔室中。称为PTEX（被输出的蛋白的镰刀形传染原虫易位子）的一个蛋白复合物过去被认为参与了这一过程，但功能证据是佐证性的和间接的。本期纳夫雷上的两篇报告采用对比性方法显示，PTEX是发病原虫蛋白向被感染细胞的布伦丹·埃尔斯沃斯（Brendan Elsworth）等人生成了PTEXΔHSP101和PTEX150的条件突变体，发现当PTEX的功能被扰动时， Josh Beck等人采用一种基于“二氢叶酸还原酶”的创新的“去稳定化域”方法来使HSP101失活，发现它是所有类别的被输出流感疾患蛋白的分泌所需的。

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  • 来源
    《Nature》 |2014年第7511期|587-591b1|共6页
  • 作者

    Brendan Elsworth; Kathryn Matthews; Catherine Q. Nie; Ming Kalanon; Sarah C. Charnaud; Paul R. Sanders; Scott A. Chisholm; Natalie A. Counihan; Philip J. Shaw; Paco Pino; Jo-Anne Chan; Mauro F. Azevedo; Stephen J. Rogerson; James G. Beeson; Brendan S. Crabb; Paul R. Gilson; Tania F. de Koning-Ward;

  • 作者单位

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia,Monash University, Clayton, Victoria, 3800, Australia;

    Deakin University, Waurn Ponds, 3216, Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia;

    Deakin University, Waurn Ponds, 3216, Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia,Monash University, Clayton, Victoria, 3800, Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia;

    Deakin University, Waurn Ponds, 3216, Australia;

    Deakin University, Waurn Ponds, 3216, Australia;

    National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani 12120, Thailand;

    The University of Geneva, 1211 Geneva 4, Switzerland;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia;

    The University of Melbourne, Parkville, Victoria, 3010 Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia,Monash University, Clayton, Victoria, 3800, Australia,The University of Melbourne, Parkville, Victoria, 3010 Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia,Monash University, Clayton, Victoria, 3800, Australia,The University of Melbourne, Parkville, Victoria, 3010 Australia;

    Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Australia,Monash University, Clayton, Victoria, 3800, Australia;

    Deakin University, Waurn Ponds, 3216, Australia;

  • 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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