Efficient invasion by Toxoplasma depends on the subversion of host protein networks
Efficient invasion by Toxoplasma depends on the subversion of host protein networks
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DOI：
10.1038/s41564-017-0018-1
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发表时间：
2017-10-01
影响因子：
28.3
通讯作者：
Lebrun, Maryse
中科院分区：
文献类型：
--
作者：
Guerin, Amandine;Corrales, Rosa Milagros;Lebrun, Maryse
Apicomplexan寄生虫是人类和家畜的重要病原体，包括疟原虫(疟疾的病原体)和弓形虫，弓形虫是弓形虫病的罪魁祸首。它们在动物宿主的细胞内复制，通过一种独特的寄生虫驱动的入侵过程获得对宿主的访问。在入侵机器的核心是在入侵寄生虫和宿主细胞之间的界面上的一个结构，称为移动连接(MJ)(1)。MJ既是进入宿主细胞的分子通道，也是使寄生虫能够启动其运动机械以驱动宿主细胞(2)的渗透，最终产生保护性液泡(3)的锚定点。MJ是通过寄生虫蛋白在寄生虫-宿主界面上的自组装建立的(4)。然而，目前尚不清楚宿主蛋白是否被颠覆以形成MJ。在这里，我们发现弓形虫棒状体颈蛋白(RON2、RON4和RON5)在入侵过程中协同作用，主动将宿主CIN85、CD2AP以及ESCRT-I组分Alix和TSG101招募到MJ。我们详细地映射了相互作用，并证明了寄生虫以显着的特异性模拟和颠覆保守的结合界面。无法招募这些宿主蛋白的寄生虫突变体在培养中显示出宿主细胞的低效入侵，并降低了小鼠的毒力。这项研究揭示了寄生虫颠覆广泛保守的宿主机制以迫使高效的宿主细胞访问的分子机制。
Apicomplexan parasites are important pathogens of humans and domestic animals, including Plasmodium species (the agents of malaria) and Toxoplasma gondii, which is responsible for toxoplasmosis. They replicate within the cells of their animal hosts, to which they gain access using a unique parasite-driven invasion process. At the core of the invasion machine is a structure at the interface between the invading parasite and host cell called the moving junction (MJ)(1). The MJ serves as both a molecular doorway to the host cell and an anchor point enabling the parasite to engage its motility machinery to drive the penetration of the host cell(2), ultimately yielding a protective vacuole(3). The MJ is established through self-assembly of parasite proteins at the parasite-host interface(4). However, it is unknown whether host proteins are subverted for MJ formation. Here, we show that Toxoplasma parasite rhoptry neck proteins (RON2, RON4 and RON5) cooperate to actively recruit the host CIN85, CD2AP and the ESCRT-I components ALIX and TSG101 to the MJ during invasion. We map the interactions in detail and demonstrate that the parasite mimics and subverts conserved binding interfaces with remarkable specificity. Parasite mutants unable to recruit these host proteins show inefficient host cell invasion in culture and attenuated virulence in mice. This study reveals molecular mechanisms by which parasites subvert widely conserved host machinery to force highly efficient host cell access.