Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia.
Commun Biol. 2023 Aug 18;6(1):861. doi: 10.1038/s42003-023-05233-y.
The malaria parasite uses actin-based mechanisms throughout its lifecycle to control a range of biological processes including intracellular trafficking, gene regulation, parasite motility and invasion. In this work we assign functions to the Plasmodium falciparum formins 1 and 2 (FRM1 and FRM2) proteins in asexual and sexual blood stage development. We show that FRM1 is essential for merozoite invasion and FRM2 is required for efficient cell division. We also observed divergent functions for FRM1 and FRM2 in gametocyte development. Conditional deletion of FRM1 leads to a delay in gametocyte stage progression. We show that FRM2 controls the actin and microtubule cytoskeletons in developing gametocytes, with premature removal of the protein resulting in a loss of transmissible stage V gametocytes. Lastly, we show that targeting formin proteins with the small molecule inhibitor of formin homology domain 2 (SMIFH2) leads to a multistage block in asexual and sexual stage parasite development.
疟原虫在其生命周期中利用基于肌动蛋白的机制来控制一系列生物过程，包括细胞内运输、基因调控、寄生虫运动和入侵。在这项工作中，我们在无性和有性血期发育中为恶性疟原虫形成蛋白 1 和 2（FRM1 和 FRM2）分配功能。我们表明 FRM1 对于裂殖子入侵是必不可少的，而 FRM2 对于有效细胞分裂是必需的。我们还观察到 FRM1 和 FRM2 在配子体发育中的功能分化。FRM1 的条件缺失导致配子体阶段进展延迟。我们表明 FRM2 控制着发育中的配子体中的肌动蛋白和微管细胞骨架，过早去除该蛋白会导致可传播的第五阶段配子体丢失。最后，我们表明，用成纤维细胞形态发生同源结构域 2（SMIFH2）的小分子抑制剂靶向形成蛋白会导致无性和有性阶段寄生虫发育的多阶段阻断。
