A cyclic GMP signalling module that regulates gliding motility in a malaria parasite.
A cyclic GMP signalling module that regulates gliding motility in a malaria parasite.
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DOI：
10.1371/journal.ppat.1000599
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发表时间：
2009-09
期刊：
影响因子：
6.7
通讯作者：
Billker O
中科院分区：
文献类型：
--
作者：
Moon RW;Taylor CJ;Bex C;Schepers R;Goulding D;Janse CJ;Waters AP;Baker DA;Billker O
动动子是疟疾生命周期中的一个运动阶段，在受精卵的蚊子血粉中形成。 Ookinetes 使用肌动球蛋白马达滑向并穿透中肠壁以在载体中建立感染。人们对滑翔运动的调节知之甚少。通过遗传相互作用研究，我们在这里描述了一个信号模块，该模块将鸟苷 3', 5'-环单磷酸 (cGMP) 识别为调节动动体分化和运动的重要第二信使。在缺乏环核苷酸降解磷酸二酯酶 δ (PDEδ) 的动动分子中，cGMP 信号不受调控，导致正常香蕉形细胞被围成圆形。这种表型在另外缺乏鸟苷酸环化酶 β (GCβ) 的双突变体中受到抑制，表明在动合子中 GCβ 是 cGMP 的重要来源，而 PDEδ 是相关的 cGMP 降解酶。在缺乏钙依赖性蛋白激酶 3 的突变体中，cGMP 依赖性蛋白激酶 PKG 的抑制会阻止滑动，而通过 cGMP 增强的信号传导可恢复正常的滑动速度，这表明钙依赖性途径和 cGMP 依赖性途径之间至少存在部分重叠。这些数据表明，在疟疾传播给蚊子的过程中，cGMP（最有可能是 PKG）信号传导在动态调节动动分子滑动方面发挥着重要作用。疟疾寄生虫是单细胞生物，必须在脊椎动物和蚊子宿主之间交替才能生存和传播。在这两种宿主中，某些寄生虫阶段可以滑过组织并侵入细胞。为滑翔和入侵提供动力的分子马达的许多组件都是已知的，我们很清楚这些组件如何相互作用以产生力。人们不太清楚电机是如何组装的，以及如何调节其零部件来打开和关闭电机的。我们已经开始在动动动物阶段解决这些问题，动动动物阶段是一种寄生虫阶段，它在蚊子的血粉中形成，并依靠滑翔穿透肠壁。使用啮齿动物的疟原虫，我们检查了删除参与控制细胞内信号分子环磷酸鸟苷 (cGMP) 水平的候选基因的效果。我们表明，cGMP 产生和降解之间的正确平衡对于动动动物的滑动非常重要，同时也保持其典型的细胞形状。然而，cGMP 的总体水平在突变体中并没有受到太大影响，因此我们相信信使要么在细胞内局部发挥作用，要么仅在寄生虫滑行时发挥作用。
The ookinete is a motile stage in the malaria life cycle which forms in the mosquito blood meal from the zygote. Ookinetes use an acto-myosin motor to glide towards and penetrate the midgut wall to establish infection in the vector. The regulation of gliding motility is poorly understood. Through genetic interaction studies we here describe a signalling module that identifies guanosine 3′, 5′-cyclic monophosphate (cGMP) as an important second messenger regulating ookinete differentiation and motility. In ookinetes lacking the cyclic nucleotide degrading phosphodiesterase δ (PDEδ), unregulated signalling through cGMP results in rounding up of the normally banana-shaped cells. This phenotype is suppressed in a double mutant additionally lacking guanylyl cyclase β (GCβ), showing that in ookinetes GCβ is an important source for cGMP, and that PDEδ is the relevant cGMP degrading enzyme. Inhibition of the cGMP-dependent protein kinase, PKG, blocks gliding, whereas enhanced signalling through cGMP restores normal gliding speed in a mutant lacking calcium dependent protein kinase 3, suggesting at least a partial overlap between calcium and cGMP dependent pathways. These data demonstrate an important function for signalling through cGMP, and most likely PKG, in dynamically regulating ookinete gliding during the transmission of malaria to the mosquito. Malaria parasites are single celled organisms, which must alternate between vertebrate and mosquito hosts to survive and spread. In both hosts, certain parasite stages can glide through tissues and invade cells. Many components of the molecular motor that powers gliding and invasion are known and we have a good idea how these may interact to generate force. It is less well understood how the motor is assembled and how its component parts are regulated to switch it on and off. We have begun to address these questions in the ookinete, a parasite stage, which forms in the blood meal of a mosquito and relies on gliding to penetrate the gut wall. Using a malaria parasite of rodents, we have examined the effect of deleting candidate genes involved in controlling levels of the intracellular signalling molecule cyclic guanosine monophosphate (cGMP). We show that the right balance between cGMP production and degradation is important for ookinetes to glide, while also maintaining their typical cell shape. Overall levels of cGMP are not much affected in the mutants, though, and we therefore believe the messenger exerts its effect either locally within the cell or only while the parasite is gliding.
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