PTEX is an essential nexus for protein export in malaria parasites
PTEX is an essential nexus for protein export in malaria parasites
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DOI：
10.1038/nature13555
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发表时间：
2014-07-30
期刊：
影响因子：
64.8
通讯作者：
de Koning-Ward, Tania F.
中科院分区：
文献类型：
--
作者：
Elsworth, Brendan;Matthews, Kathryn;de Koning-Ward, Tania F.
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（1-6）。这些蛋白质具有多种对毒力或寄生虫生长至关重要的作用（7）。人们对了解蛋白质是如何出口的以及常见的机制是否参与了不同类别的出口蛋白质的运输有着浓厚的兴趣（8，9）。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易位子（PTEX）（10）。尽管PTEX与一类输出蛋白质的输出有关（10，11），但没有直接证据表明其在蛋白质易位中的作用和范围。在这里，我们显示，通过产生两个基本PTEX组分（HSP 101或PTEX 150）缺陷的寄生虫系，并分析缺乏非必需组分TRX 2的系（参考文献12），大大减少了所有类别的输出蛋白质越过包裹寄生虫的双膜屏障的运输。这包括含有PEXEL基序（RxLxE/Q/D）的蛋白质（1，2）和PEXEL阴性输出蛋白质（PNEP）（6）。此外，出口的蛋白质注定表达在感染的红细胞表面，包括恶性疟原虫中的主要毒力因子PfEMP 1，显着减少PTEX敲低寄生虫。PTEX功能对于血液阶段的生长也是必不可少的，因为即使是PTEX组分的适度敲低也对寄生虫在体外和体内完成红细胞周期的能力产生强烈影响。因此，作为疟原虫寄生虫中蛋白质输出的唯一已知联系，以及一种重要的酶机器，PTEX是主要的药物靶标。
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(1-6). These proteins have a variety of roles that are essential to virulence or parasite growth(7). There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins(8,9). One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX)(10). Although PTEX has been linked to the export of one class of exported proteins(10,11), 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)(1,2) and PEXEL-negative exported proteins (PNEPs)(6). 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.