Malaria Parasite Schizont Egress Antigen-1 Plays an Essential Role in Nuclear Segregation during Schizogony.
Malaria Parasite Schizont Egress Antigen-1 Plays an Essential Role in Nuclear Segregation during Schizogony.
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DOI：
10.1128/mbio.03377-20
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发表时间：
2021-03-09
期刊：
影响因子：
6.4
通讯作者：
Blackman MJ
中科院分区：
文献类型：
--
作者：
Perrin AJ;Bisson C;Faull PA;Renshaw MJ;Lees RA;Fleck RA;Saibil HR;Snijders AP;Baker DA;Blackman MJ
疟疾是一种致命的传染病。合理设计新的治疗方法将是控制和根除的关键。疟疾寄生虫通过红细胞内增殖的重复循环引起疾病。在每个循环中，几轮DNA复制产生多核形式，称为裂殖子，其经历分割以形成子裂殖子。当感染细胞破裂时，裂殖子外出侵入新的红细胞并重复该循环。在人类疟疾感染中，恶性疟原虫蛋白PF3D7_1021800的特异性抗体反应先前与预防疟疾有关，导致人们对PF3D7_1021800作为候选疫苗抗原产生了兴趣。据报道，该蛋白质的抗体可抑制出口，因此将其命名为出口抗原-1（SEA 1）。一项单独的研究发现，SEA 1以依赖于寄生虫cGMP依赖性蛋白激酶PKG的方式进行磷酸化，从而触发出口。虽然这些发现暗示了SEA 1在裂殖子排出中的作用，但这种蛋白质也与裂殖体发育过程中的动粒功能有关。因此，SEA 1的功能仍不清楚。在这里，我们表明，恶性疟原虫SEA 1定位在分裂的细胞核内的着丝粒附近，SEA 1表达的条件性中断严重影响DNA的分布和裂殖子的形成，裂殖体发育过程中，与一部分SEA 1无效裂殖子完全缺乏细胞核。SEA 1-null突变体破裂，尽管效率较低，表明SEA 1功能和正常分割都不是出口的先决条件。我们的结论是，SEA 1不发挥直接的机械出口的作用，而是作为一个必要的监管机构，以确保正确的包装核裂殖子内的出口上游。
Malaria is a deadly infectious disease. Rationally designed novel therapeutics will be essential for its control and eradication. Malaria parasites cause disease through repeated cycles of intraerythrocytic proliferation. Within each cycle, several rounds of DNA replication produce multinucleated forms, called schizonts, that undergo segmentation to form daughter merozoites. Upon rupture of the infected cell, the merozoites egress to invade new erythrocytes and repeat the cycle. In human malarial infections, an antibody response specific for the Plasmodium falciparum protein PF3D7_1021800 was previously associated with protection against malaria, leading to an interest in PF3D7_1021800 as a candidate vaccine antigen. Antibodies to the protein were reported to inhibit egress, resulting in it being named schizont egress antigen-1 (SEA1). A separate study found that SEA1 undergoes phosphorylation in a manner dependent upon the parasite cGMP-dependent protein kinase PKG, which triggers egress. While these findings imply a role for SEA1 in merozoite egress, this protein has also been implicated in kinetochore function during schizont development. Therefore, the function of SEA1 remains unclear. Here, we show that P. falciparum SEA1 localizes in proximity to centromeres within dividing nuclei and that conditional disruption of SEA1 expression severely impacts the distribution of DNA and formation of merozoites during schizont development, with a proportion of SEA1-null merozoites completely lacking nuclei. SEA1-null schizonts rupture, albeit with low efficiency, suggesting that neither SEA1 function nor normal segmentation is a prerequisite for egress. We conclude that SEA1 does not play a direct mechanistic role in egress but instead acts upstream of egress as an essential regulator required to ensure the correct packaging of nuclei within merozoites.