Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death.
Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death.
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DOI：
10.7554/elife.56773
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发表时间：
2020-09-25
期刊：
影响因子：
7.7
通讯作者：
Derbyshire E
中科院分区：
文献类型：
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作者：
Lu KY;Pasaje CFA;Srivastava T;Loiselle DR;Niles JC;Derbyshire E
恶性疟原虫中磷脂酰肌醇3-磷酸（PI(3)P）水平与对青蒿素和环境因素引起的细胞应激的耐受性相关。然而，PI(3)P函数在疟原虫应激反应中的作用尚不清楚。在这里，我们使用PI3K抑制剂和抗疟疾药物来研究PI(3)P在热条件下重现疟疾热的重要性。利用活细胞显微镜的化学和基因报告显示，PI(3)P在热应激下稳定消化液泡（DV）。我们证明了在PI(3)缺磷的恶性疟原虫中，热诱导的DV失稳发生在细胞死亡之前，并且在退出应激条件和PI3K抑制剂后是可逆的。化学蛋白质组学方法鉴定PfHsp70-1为PI(3) p结合蛋白。一种Hsp70抑制剂及热休克条件下PfHsp70-1表型PI(3)缺磷寄生虫的抑制此外，PfHsp70-1下调使寄生虫对热休克和PI3K抑制剂过敏。我们的研究结果强调了PI(3)P和PfHsp70-1之间的机制联系，并提出了一种新的PI(3)P在热应激下DV稳定中的功能。
Phosphatidylinositol 3-phosphate (PI(3)P) levels in Plasmodium falciparum correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the Plasmodium stress response was unknown. Here, we used PI3K inhibitors and antimalarial agents to examine the importance of PI(3)P under thermal conditions recapitulating malarial fever. Live cell microscopy using chemical and genetic reporters revealed that PI(3)P stabilizes the digestive vacuole (DV) under heat stress. We demonstrate that heat-induced DV destabilization in PI(3)P-deficient P. falciparum precedes cell death and is reversible after withdrawal of the stress condition and the PI3K inhibitor. A chemoproteomic approach identified PfHsp70-1 as a PI(3)P-binding protein. An Hsp70 inhibitor and knockdown of PfHsp70-1 phenocopy PI(3)P-deficient parasites under heat shock. Furthermore, PfHsp70-1 downregulation hypersensitizes parasites to heat shock and PI3K inhibitors. Our findings underscore a mechanistic link between PI(3)P and PfHsp70-1 and present a novel PI(3)P function in DV stabilization during heat stress.