Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress.
Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress.
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DOI：
10.1371/journal.ppat.1003344
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发表时间：
2013-05
期刊：
影响因子：
6.7
通讯作者：
Blackman MJ
中科院分区：
文献类型：
--
作者：
Collins CR;Hackett F;Strath M;Penzo M;Withers-Martinez C;Baker DA;Blackman MJ
疟原虫在红细胞内寄生虫空泡（PV）内复制。最终，在一个被称为出口的严格调控过程中，PV和细胞内裂殖子表面的蛋白质被称为PfSUB1的必需寄生虫丝氨酸蛋白酶修饰，同时封闭的PV和红细胞膜破裂，释放裂殖子侵入新鲜的红细胞。恶性疟原虫cGMP依赖性蛋白激酶（PfPKG）的抑制阻止了出口，但其潜在机制尚不清楚。在这里，我们表明PfPKG活性是PfSUB1释放到PV以及释放称为微丝的不同裂殖子细胞器所必需的。通过抑制寄生虫磷酸二酯酶活性来刺激PfPKG可诱导发育不成熟的非侵入性寄生虫过早排出PfSUB1。我们的研究结果确定了调节PfSUB1功能和出口的信号通路，并提高了在治疗方法中靶向PfPKG或寄生虫磷酸二酯酶以失调寄生虫生命周期中关键蛋白酶介导步骤的可能性。疟疾是发展中国家的一个祸害，许多研究人员正在寻找治疗和控制这种疾病的新方法。疟疾是由一种生长在红细胞内的单细胞寄生虫引起的，这种寄生虫最终会使红细胞破裂，在一个被称为出口的过程中释放出侵入性的裂殖子。在早期的工作中，我们发现，就在外出之前，一种称为SUB1的酶从细胞内寄生虫释放到它们所居住的液泡中。SUB1然后切割侵入性裂殖子的排出和发育所需的许多蛋白质。控制SUB1放电的信号知之甚少。在这项工作中，我们表明SUB1的释放需要另一种称为蛋白激酶G（PKG）的寄生虫酶的活性，这种酶反过来又被一种称为cGMP的小分子激活。PKG的抑制阻断了SUB1的排出和排出，而PKG被称为磷酸二酯酶抑制剂的一类化合物的成员过早激活，这会增加寄生虫中的cGMP水平，诱导大多数非侵入性裂殖子的过早排出。这些发现增加了我们对出口的理解，并表明疟疾PKG和寄生虫磷酸二酯酶（在人类中是经验证的药物靶点）都是一类新的抗疟药物的潜在靶点。
The malaria parasite replicates within an intraerythrocytic parasitophorous vacuole (PV). Eventually, in a tightly regulated process called egress, proteins of the PV and intracellular merozoite surface are modified by an essential parasite serine protease called PfSUB1, whilst the enclosing PV and erythrocyte membranes rupture, releasing merozoites to invade fresh erythrocytes. Inhibition of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) prevents egress, but the underlying mechanism is unknown. Here we show that PfPKG activity is required for PfSUB1 discharge into the PV, as well as for release of distinct merozoite organelles called micronemes. Stimulation of PfPKG by inhibiting parasite phosphodiesterase activity induces premature PfSUB1 discharge and egress of developmentally immature, non-invasive parasites. Our findings identify the signalling pathway that regulates PfSUB1 function and egress, and raise the possibility of targeting PfPKG or parasite phosphodiesterases in therapeutic approaches to dysregulate critical protease-mediated steps in the parasite life cycle. Malaria is a scourge of the developing world and many researchers are seeking new ways to treat and control the disease. Malaria is caused by a single-celled parasite that grows within red blood cells, eventually rupturing them to release invasive merozoites in a process known as egress. In earlier work we found that, just prior to egress, an enzyme called SUB1 is released from the intracellular parasites into the vacuole in which they reside. SUB1 then cleaves a number of proteins required for egress and development of invasive merozoites. The signals that control SUB1 discharge are poorly understood. In this work, we show that SUB1 release requires the activity of another parasite enzyme called protein kinase G (PKG), which is in turn activated by a small molecule called cGMP. Inhibition of PKG blocks SUB1 discharge and egress, whilst premature activation of PKG by a member of a class of compounds called phosphodiesterase inhibitors, which increase cGMP levels in the parasite, induces premature egress of mostly non-invasive merozoites. These findings increase our understanding of egress and show that both malarial PKG and parasite phosphodiesterases (which are validated drug targets in humans) are potential targets for a new class of antimalarial drugs.
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3
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