Loss-of-function analyses defines vital and redundant functions of the Plasmodium rhomboid protease family
Loss-of-function analyses defines vital and redundant functions of the Plasmodium rhomboid protease family
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DOI：
10.1111/mmi.12187
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发表时间：
2013-04-01
影响因子：
3.6
通讯作者：
Khan, Shahid M.
中科院分区：
文献类型：
--
作者：
Lin, Jing-wen;Meireles, Patricia;Khan, Shahid M.
菱形样蛋白酶在其跨膜结构域内切割膜锚定蛋白。在顶复门寄生虫中，底物包括在寄生虫运动和宿主细胞侵入中起作用的分子。虽然两个疟原虫菱形，ROM 1和ROM 4，已被检查，其余六个菱形疟疾寄生虫的生命周期中的作用是未知的。我们提出了系统的基因缺失分析的所有八个疟原虫菱形样蛋白作为一种手段，以发现阶段特异性表型和潜在的功能，在啮齿动物疟疾模型，伯氏疟原虫。四个菱形（ROM 4，6，7和8）是难治基因缺失，表明在无性血液阶段的发展至关重要的作用。相比之下，ROM 1、3、9和10在血液阶段发育中表现出明显的缺陷，并且在蚊子或肝脏发育中没有表现出轻微或严重的缺陷。缺乏ROM 9和ROM 10的寄生虫没有表现出主要的表型缺陷。缺乏ROM1的寄生虫在肝脏感染后出现血液期通畅延迟，但与先前的研究相反，血液期寄生虫具有与野生型寄生虫相似的生长和毒力特征。在蚊子中缺乏ROM 3的寄生虫容易建立卵囊，但不能产生子孢子。ROM3是第一个被鉴定为在孢子生殖中起重要作用的顶复门菱形体。
Rhomboid-like proteases cleave membrane-anchored proteins within their transmembrane domains. In apicomplexan parasites substrates include molecules that function in parasite motility and host cell invasion. While two Plasmodium rhomboids, ROM1 and ROM4, have been examined, the roles of the remaining six rhomboids during the malaria parasite's life cycle are unknown. We present systematic gene deletion analyses of all eight Plasmodium rhomboid-like proteins as a means to discover stage-specific phenotypes and potential functions in the rodent malaria model, P. berghei. Four rhomboids (ROM4, 6, 7 and 8) are refractory to gene deletion, suggesting an essential role during asexual blood stage development. In contrast ROM1, 3, 9 and 10 were dispensable for blood stage development and exhibited no, subtle or severe defects in mosquito or liver development. Parasites lacking ROM9 and ROM10 showed no major phenotypic defects. Parasites lacking ROM1 presented a delay in blood stage patency following liver infection, but in contrast to a previous study blood stage parasites had similar growth and virulence characteristics as wild type parasites. Parasites lacking ROM3 in mosquitoes readily established oocysts but failed to produce sporozoites. ROM3 is the first apicomplexan rhomboid identified to play a vital role in sporogony.