The Plasmodium falciparum Hsp70-x chaperone assists the heat stress response of the malaria parasite
The Plasmodium falciparum Hsp70-x chaperone assists the heat stress response of the malaria parasite
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DOI：
10.1096/fj.201901741r
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发表时间：
2019-12-01
期刊：
影响因子：
4.8
通讯作者：
Vakonakis, Ioannis
中科院分区：
文献类型：
--
作者：
Day, Jemma;Passecker, Armin;Vakonakis, Ioannis
恶性疟原虫是最致命的人类感染性疟疾寄生虫。恶性疟原虫疟疾的一个标志是寄生虫对宿主红细胞的广泛重塑，这促进了毒力特性的发展，例如宿主细胞粘附到微血管的内皮衬里。宿主重塑由大量输出到红细胞的寄生虫蛋白质介导;其中有一种单一的热休克蛋白（Hsp）70类蛋白伴侣，恶性疟原虫Hsp 70-x（PfHsp 70-x）。PfHsp 70-x以前被证明有助于毒性细胞粘附特性的发展。在这里，我们表明，PfHsp 70-x也支持寄生虫生长在高温条件下，模拟发热事件，特别是在寄生虫生命周期的开始时，大多数宿主细胞重塑发生。PfHsp 70-x的生化和生物物理分析，包括其催化结构域和其刺激性Hsp 40伴侣蛋白的J-结构域的晶体结构，表明PfHsp 70-x是高度相似的人Hsp 70伴侣蛋白内源性红细胞。然而，我们的研究结果表明，选择性抑制PfHsp 70-x功能，使用小分子可能是可能的，并突出其催化结构域的特定位点作为潜在的高度关注。我们讨论了PfHsp 70-x和人类伴侣在恶性疟原虫生物学中的可能作用，以及特异性抑制剂如何帮助我们解开它们的相对贡献。
Plasmodium falciparum is the most lethal of human-infective malaria parasites. A hallmark of P. falciparum malaria is extensive remodeling of host erythrocytes by the parasite, which facilitates the development of virulence properties such as host cell adhesion to the endothelial lining of the microvasculature. Host remodeling is mediated by a large complement of parasite proteins exported to the erythrocyte; among them is a single heat shock protein (Hsp)70-class protein chaperone, P. falciparum Hsp70-x (PfHsp70-x). PfHsp70-x was previously shown to assist the development of virulent cytoadherence characteristics. Here, we show that PfHsp70-x also supports parasite growth under elevated temperature conditions that simulate febrile episodes, especially at the beginning of the parasite life cycle when most of host cell remodeling takes place. Biochemical and biophysical analyses of PfHsp70-x, including crystallographic structures of its catalytic domain and the J-domain of its stimulatory Hsp40 cochaperone, suggest that PfHsp70-x is highly similar to human Hsp70 chaperones endogenous to the erythrocyte. Nevertheless, our results indicate that selective inhibition of PfHsp70-x function using small molecules may be possible and highlight specific sites of its catalytic domain as potentially of high interest. We discuss the likely roles of PfHsp70-x and human chaperones in P. falciparum biology and how specific inhibitors may assist us in disentangling their relative contributions.