A schistosome cAMP-dependent protein kinase catalytic subunit is essential for parasite viability.
A schistosome cAMP-dependent protein kinase catalytic subunit is essential for parasite viability.
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DOI：
10.1371/journal.pntd.0000505
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发表时间：
2009-08-25
影响因子：
3.8
通讯作者：
Davies SJ
中科院分区：
文献类型：
--
作者：
Swierczewski BE;Davies SJ
真核生物、原生动物和蠕虫寄生虫广泛使用蛋白激酶来控制细胞功能，这表明蛋白激酶可能是开发抗寄生虫药物的新靶点。由于它们在细胞内信号传导途径中的中心作用，环核苷酸依赖性激酶如cAMP依赖性蛋白激酶（PKA）代表用于治疗寄生虫感染和肿瘤性疾病的有希望的新靶点。然而，这些激酶在染色体生物学中的作用尚未被表征，编码染色体PKA的基因尚未被鉴定。在这里，我们提供的PKA信号通路在成人曼氏血吸虫的存在，并显示PKA活性所需的寄生虫在体外的生存能力的生化证据。我们还提供了第一个完整的描述基因编码的PKA催化亚基在S。mansoni，命名为SmPKA-C。最后，我们证明，通过RNA干扰，SmPKA-C有助于PKA活性，我们检测到的生化和SmPKA-C表达的抑制在成人寄生虫死亡的结果。总之，我们的数据表明，SmPKA-C是一个非常重要的基因产物，并可能代表一个有吸引力的治疗和控制血吸虫病的治疗靶点。血吸虫是寄生在循环系统中的寄生性扁形虫，是全世界数百万人衰弱和潜伏疾病的原因。像其他复杂的生物体一样，寄生虫和其他寄生蠕虫通过广泛使用称为蛋白激酶的酶来调节它们的细胞生物学，这些酶使其他蛋白质磷酸化以改变它们的功能。一种这样的蛋白激酶，cAMP依赖性蛋白激酶（PKA），已经被提出作为治疗寄生虫感染和癌症的治疗靶标。在这里，我们使用生物化学技术，以显示寄生蠕虫具有一个功能PKA途径，需要生存的寄生虫。我们还确定了一个寄生虫基因，编码一个功能性PKA酶，并表明，沉默该基因的结果在两个显着的损失PKA活性在寄生虫蠕虫和寄生虫死亡。这些研究结果表明，我们已经确定的基因是至关重要的，它的蛋白质产物可能是一个目标，为开发急需的新药物来治疗染色体感染。
Eukaryotes, protozoan, and helminth parasites make extensive use of protein kinases to control cellular functions, suggesting that protein kinases may represent novel targets for the development of anti-parasitic drugs. Because of their central role in intracellular signaling pathways, cyclic nucleotide–dependent kinases such as cAMP-dependent protein kinase (PKA) represent promising new targets for the treatment of parasitic infections and neoplastic disorders. However, the role of these kinases in schistosome biology has not been characterized and the genes encoding schistosome PKAs have not been identified. Here we provide biochemical evidence for the presence of a PKA signaling pathway in adult Schistosoma mansoni and show that PKA activity is required for parasite viability in vitro. We also provide the first full description of a gene that encodes a PKA catalytic subunit in S. mansoni, named SmPKA-C. Finally we demonstrate, through RNA interference, that SmPKA-C contributes to the PKA activity we detected biochemically and that inhibition of SmPKA-C expression in adult schistosomes results in parasite death. Together our data show that SmPKA-C is a critically important gene product and may represent an attractive therapeutic target for the treatment and control of schistosomiasis. Schistosomes are parasitic flatworms that inhabit the circulatory system and are the cause of a debilitating and insidious disease for millions of people worldwide. Like other complex organisms, schistosomes and other parasitic worms regulate their cell biology through extensive use of enzymes called protein kinases that phosphorylate other proteins to alter their function. One such protein kinase, cAMP-dependent protein kinase (PKA), has been proposed as a therapeutic target for the treatment of parasitic infections and cancer. Here we use biochemical techniques to show that schistosome worms possess a functional PKA pathway that is required for survival of the parasites. We also identify a parasite gene that encodes a functional PKA enzyme and show that silencing this gene results in both significant loss of PKA activity in schistosome worms and parasite death. These findings suggest that the gene we have identified is critically important to schistosomes and that its protein product may represent a target for the development of much-needed new drugs to treat schistosome infections.
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