Divergent roles for the RH5 complex components, CyRPA and RIPR in human-infective malaria parasites
Divergent roles for the RH5 complex components, CyRPA and RIPR in human-infective malaria parasites
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DOI：
10.1371/journal.ppat.1007809
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发表时间：
2019-06-01
期刊：
影响因子：
6.7
通讯作者：
Holder, Anthony A.
中科院分区：
文献类型：
--
作者：
Knuepfer, Ellen;Wright, Katherine E.;Holder, Anthony A.
疟疾是由疟原虫引起的，这种寄生虫入侵并在红细胞中复制。恶性疟原虫是导致人类严重疟疾的主要原因，由PfCyRPA、PfRIPR和PfRh5组成的异源三聚体复合体通过PfRh5和红细胞受体basigin(BSG)的相互作用对红细胞的侵袭是必不可少的。然而，虽然CyRPA和RIPR存在于大多数疟原虫物种中，但RH5只在小的紫锥虫亚属中发现。然而，针对BSG的PfRh5-PfCyRPA-PfRIPR的复合体的存在，以及CyRPA和RIPR在入侵中的参与，在非紫菜属寄生虫中尚未得到解决。在这里，我们确定与恶性疟原虫不同，诺氏疟原虫和间日疟原虫并不普遍需要BSG作为宿主细胞入侵受体。虽然我们发现PkCyRPA和PkRIPR都是诺氏疟原虫在体外成功入侵红细胞所必需的，但这两种蛋白都不能相互形成复合体，也不能与RH5类分子形成复合体。相反，PkRIPR是另一个三聚体蛋白质复合体的一部分，而PkCyRPA似乎没有其他寄生虫结合伙伴的作用。因此，在没有RH5的情况下，在紫锥虫亚属之外，RIPR和CyRPA具有不同的独立功能，对寄生虫的生存至关重要。作者摘要疟疾是最具破坏性的传染病之一，给人类造成重大痛苦和死亡。它是由疟原虫属的寄生虫在血液中繁殖引起的。了解红细胞侵袭的机制是开发新的干预策略的关键。恶性疟原虫是最严重的疟疾形式，它需要一个三聚体蛋白复合体RH5-CyRPA-RIPR与宿主受体BSG相互作用才能成功入侵。我们在这里表明，BSG受体对于人类疟疾的另外两个主要原因间日疟原虫和诺氏疟原虫的入侵并不是必不可少的。此外，我们还分析了在诺氏疟原虫中没有RH5样分子的情况下，CyRPA和RIPR的作用，结果表明，与恶性疟原虫中RH5的存在不同，这些分子不会相互作用而形成蛋白质复合体。PkRIPR是另一种蛋白质复合体的一部分。尽管存在这种差异，但CyRPA和RIPR在其他重要的人类疟疾致病寄生虫的宿主细胞入侵过程中仍然具有重要的功能。
Malaria is caused by Plasmodium parasites, which invade and replicate in erythrocytes. For Plasmodium falciparum, the major cause of severe malaria in humans, a heterotrimeric complex comprised of the secreted parasite proteins, PfCyRPA, PfRIPR and PfRH5 is essential for erythrocyte invasion, mediated by the interaction between PfRH5 and erythrocyte receptor basigin (BSG). However, whilst CyRPA and RIPR are present in most Plasmodium species, RH5 is found only in the small Laverania subgenus. Existence of a complex analogous to PfRH5-PfCyRPA-PfRIPR targeting BSG, and involvement of CyRPA and RIPR in invasion, however, has not been addressed in non-Laverania parasites. Here, we establish that unlike P. falciparum, P. knowlesi and P. vivax do not universally require BSG as a host cell invasion receptor. Although we show that both PkCyRPA and PkRIPR are essential for successful invasion of erythrocytes by P. knowlesi parasites in vitro, neither protein forms a complex with each other or with an RH5-like molecule. Instead, PkRIPR is part of a different trimeric protein complex whereas PkCyRPA appears to function without other parasite binding partners. It therefore appears that in the absence of RH5, outside of the Laverania subgenus, RIPR and CyRPA have different, independent functions crucial for parasite survival.Author summary Malaria is one of the most devastating infectious diseases, causing significant human suffering and death. It is caused by parasites of the genus Plasmodium proliferating in the bloodstream. Understanding the mechanism of erythrocyte invasion is key for developing novel intervention strategies. P. falciparum, the cause of the most severe form of malaria, requires the interaction of a trimeric protein complex RH5-CyRPA-RIPR with the host receptor BSG for successful invasion. We show here that the BSG receptor is not essential for invasion by two other major causes of human malaria, P. vivax and P. knowlesi. Furthermore, we analyzed the role of CyRPA and RIPR in the absence of an RH5-like molecule in P. knowlesi and show that these molecules do not associate to form a protein complex unlike in the presence of RH5 in P. falciparum. PkRIPR is part of a different protein complex. Despite this difference CyRPA and RIPR still have essential functions during host cell invasion in other important human malaria-causing parasites.