Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom.
Malaria Parasitology Laboratory, The Francis Crick Institute, London, United Kingdom.
PLoS Pathog. 2019 Sep 6;15(9):e1008049. doi: 10.1371/journal.ppat.1008049. eCollection 2019 Sep.
The malaria parasite Plasmodium falciparum invades, replicates within and destroys red blood cells in an asexual blood stage life cycle that is responsible for clinical disease and crucial for parasite propagation. Invasive malaria merozoites possess a characteristic apical complex of secretory organelles that are discharged in a tightly controlled and highly regulated order during merozoite egress and host cell invasion. The most prominent of these organelles, the rhoptries, are twinned, club-shaped structures with a body or bulb region that tapers to a narrow neck as it meets the apical prominence of the merozoite. Different protein populations localise to the rhoptry bulb and neck, but the function of many of these proteins and how they are spatially segregated within the rhoptries is unknown. Using conditional disruption of the gene encoding the only known glycolipid-anchored malarial rhoptry bulb protein, rhoptry-associated membrane antigen (RAMA), we demonstrate that RAMA is indispensable for blood stage parasite survival. Contrary to previous suggestions, RAMA is not required for trafficking of all rhoptry bulb proteins. Instead, RAMA-null parasites display selective mislocalisation of a subset of rhoptry bulb and neck proteins (RONs) and produce dysmorphic rhoptries that lack a distinct neck region. The mutant parasites undergo normal intracellular development and egress but display a fatal defect in invasion and do not induce echinocytosis in target red blood cells. Our results indicate that distinct pathways regulate biogenesis of the two main rhoptry sub-compartments in the malaria parasite.
疟原虫恶性疟原虫在无性血期生命周期中入侵、复制并破坏红细胞，这是导致临床疾病的主要原因，也是寄生虫繁殖的关键。入侵性疟原虫裂殖子具有特征性的顶端复合物分泌细胞器，在裂殖子逸出和宿主细胞入侵过程中以紧密控制和高度调节的顺序释放。这些细胞器中最突出的是棒状体，是孪生的、棒状结构，具有一个体部或球部区域，在与裂殖子的顶端突起相遇时逐渐变细为狭窄的颈部。不同的蛋白质群体定位于棒状体的球部和颈部，但这些蛋白质的许多功能以及它们在棒状体中的空间分隔方式尚不清楚。我们通过条件性破坏编码唯一已知糖脂锚定疟原虫棒状体蛋白的基因，即棒状体相关膜抗原（RAMA），证明了 RAMA 对血液期寄生虫的生存是不可或缺的。与之前的建议相反，RAMA 不是所有棒状体蛋白运输所必需的。相反，RAMA 缺失的寄生虫显示出一部分棒状体和颈部蛋白（RON）的选择性定位错误，并且产生缺乏明显颈部区域的畸形棒状体。突变寄生虫经历正常的细胞内发育和逸出，但在入侵过程中表现出致命缺陷，并且不会在靶红细胞中诱导出棘形红细胞。我们的结果表明，不同的途径调节疟原虫中两个主要棒状体亚区的生物发生。
