Ca2+-mediated exocytosis of subtilisin-like protease 1: a key step in egress of Plasmodium falciparum merozoites
Ca2+-mediated exocytosis of subtilisin-like protease 1: a key step in egress of Plasmodium falciparum merozoites
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DOI：
10.1111/cmi.12086
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发表时间：
2013-06-01
影响因子：
3.4
通讯作者：
Singh, Shailja
中科院分区：
文献类型：
--
作者：
Agarwal, Shalini;Singh, Maneesh Kumar;Singh, Shailja
恶性疟原虫裂殖子从宿主红细胞中排出是血液期寄生虫增殖的关键步骤。蛋白水解事件的级联在导致裂殖子排出的膜降解中起主要作用。然而，调节红细胞内裂殖子成熟后蛋白酶的时间激活和/或分泌的信号仍然不清楚。在这里，我们已经测试了细胞内Ca 2+在调节恶性疟原虫裂殖子从宿主排出中的作用。通过延时视频显微镜观察到，细胞内Ca 2+在出口前急剧上升，表明细胞内Ca 2+在此过程中的作用。用螯合剂如BAPTA-AM螯合细胞内Ca 2+或用磷脂酶C（PLC）抑制剂抑制Ca 2+从细胞内储存释放阻断裂殖子排出。有趣的是，螯合胞内Ca ~（2+）也被发现阻止了一种关键蛋白酶PfSUB 1（枯草杆菌蛋白酶样蛋白酶1）从恶性疟原虫裂殖子的外消旋体释放到寄生虫空泡（PV）。这导致PfSERA 5（丝氨酸重复抗原5）的加工的抑制和寄生虫空泡膜（PVM）破裂和裂殖子排出的阻断。对调控恶性疟原虫裂殖子排出的步骤的完整理解可能为开发阻断排出和限制寄生虫生长的药物提供新的靶点。
Egress of Plasmodium falciparum merozoites from host erythrocytes is a critical step in multiplication of blood-stage parasites. A cascade of proteolytic events plays a major role in degradation of membranes leading to egress of merozoites. However, the signals that regulate the temporal activation and/or secretion of proteases upon maturation of merozoites in intra-erythrocytic schizonts remain unclear. Here, we have tested the role of intracellular Ca2+ in regulation of egress of P.falciparum merozoites from schizonts. A sharp rise in intracellular Ca2+ just before egress, observed by time-lapse video microscopy, suggested a role for intracellular Ca2+ in this process. Chelation of intracellular Ca2+ with chelators such as BAPTA-AM or inhibition of Ca2+ release from intracellular stores with a phospholipase C (PLC) inhibitor blocks merozoite egress. Interestingly, chelation of intracellular Ca2+ in schizonts was also found to block the discharge of a key protease PfSUB1 (subtilisin-like protease 1) from exonemes of P.falciparum merozoites to parasitophorous vacuole (PV). This leads to inhibition of processing of PfSERA5 (serine repeat antigen 5) and a block in parasitophorous vacuolar membrane (PVM) rupture and merozoite egress. A complete understanding of the steps regulating egress of P.falciparum merozoites may provide novel targets for development of drugs that block egress and limit parasite growth.