Hsp90 inhibitors radicicol and geldanamycin have opposing effects on Leishmania Aha1-dependent proliferation
Hsp90 inhibitors radicicol and geldanamycin have opposing effects on Leishmania Aha1-dependent proliferation
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DOI：
10.1007/s12192-017-0800-2
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发表时间：
2017-09-01
影响因子：
3.8
通讯作者：
Clos, Joachim
中科院分区：
文献类型：
--
作者：
Bartsch, Katharina;Hombach-Barrigah, Antje;Clos, Joachim
热休克蛋白90及其辅助分子伴侣是医学上重要的寄生虫杜氏利什曼原虫所必需的，促进生命周期控制和细胞内存活。Hsp90的活性受Aha1和P23家族的辅伴侣调节。本文研究了L. donovani Aha1在两个生命周期阶段，其与Hsp90的相互作用以及Aha1无效突变体在昆虫阶段和感染的巨噬细胞内的表型。这项研究提供了一个详细的在体外分析的功能Aha1利什曼原虫寄生虫和第一个实例的反向遗传分析Aha1的原生动物寄生虫。虽然Aha1在标准生长条件下和高温下是非必需的，但Aha1可以防止乙醇胁迫。然而，在Hsp90抑制剂根赤霉素（RAD）和格尔德霉素（GA）的存在下，Aha1的过度表达和缺乏都会影响寄生虫的生长。在RAD压力下，P23和Aha1以拮抗方式起作用。相比之下，在GA处理下，两种共分子伴侣的表达水平具有相似的效果，表明两种化合物的不同抑制机制。Aha1也在增强毒力的外泌体中分泌。这可能解释了为什么Aha1的缺失降低了L. donovani在离体小鼠巨噬细胞中的作用，表明在细胞内哺乳动物阶段的作用。
Hsp90 and its co-chaperones are essential for the medically important parasite Leishmania donovani, facilitating life cycle control and intracellular survival. Activity of Hsp90 is regulated by co-chaperones of the Aha1 and P23 families. In this paper, we studied the expression of L. donovani Aha1 in two life cycle stages, its interaction with Hsp90 and the phenotype of Aha1 null mutants during the insect stage and inside infected macrophages. This study provides a detailed in vitro analysis of the function of Aha1 in Leishmania parasites and the first instance of a reverse genetic analysis of Aha1 in a protozoan parasite. While Aha1 is non-essential under standard growth conditions and at elevated temperature, Aha1 protects against ethanol stress. However, both overexpression and lack of Aha1 affected parasite growth in the presence of the Hsp90 inhibitors radicicol (RAD) and geldanamycin (GA). Under RAD pressure, P23 and Aha1 act in an antagonistic way. By contrast, expression levels of both co-chaperones have similar effects under GA treatment, indicating different inhibition mechanisms by the two compounds. Aha1 is also secreted in virulence-enhancing exosomes. This may explain why the loss of Aha1 reduces the infectivity of L. donovani in ex vivo mouse macrophages, indicating a role during the intracellular mammalian stage.