Center for Infectious Disease Research, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, WA, USA.
Center for Infectious Disease Research, Seattle, WA, USA.
Cell Chem Biol. 2022 Sep 15;29(9):1419-1433.e5. doi: 10.1016/j.chembiol.2022.06.001. Epub 2022 Jun 22.
Prior to initiating symptomatic malaria, a single Plasmodium sporozoite infects a hepatocyte and develops into thousands of merozoites, in part by scavenging host resources, likely delivered by vesicles. Here, we demonstrate that host microtubules (MTs) dynamically reorganize around the developing liver stage (LS) parasite to facilitate vesicular transport to the parasite. Using a genome-wide CRISPR-Cas9 screen, we identified host regulators of cytoskeleton organization, vesicle trafficking, and ER/Golgi stress that regulate LS development. Foci of γ-tubulin localized to the parasite periphery; depletion of centromere protein J (CENPJ), a novel regulator identified in the screen, exacerbated this re-localization and increased infection. We demonstrate that the Golgi acts as a non-centrosomal MT organizing center (ncMTOC) by positioning γ-tubulin and stimulating MT nucleation at parasite periphery. Together, these data support a model where the Plasmodium LS recruits host Golgi to form MT-mediated conduits along which host organelles are recruited to PVM and support parasite development.
在出现症状性疟疾之前，单个疟原虫孢子虫感染肝细胞，并发育成数千个裂殖子，部分通过吞噬宿主资源来实现，这些资源可能是通过囊泡输送的。在这里，我们证明宿主微管（MTs）围绕发育中的肝期（LS）寄生虫动态重组，以促进囊泡向寄生虫的运输。使用全基因组 CRISPR-Cas9 筛选，我们鉴定了宿主细胞骨架组织、囊泡运输和内质网/高尔基体应激的调节剂，这些调节剂调节 LS 的发育。γ-微管蛋白的焦点定位于寄生虫的外围；在筛选中发现的新型调节因子着丝粒蛋白 J（CENPJ）的耗竭加剧了这种重定位，并增加了感染。我们证明高尔基体通过定位γ-微管蛋白和刺激寄生虫周围 MT 的核形成，充当非中心体 MT 组织中心（ncMTOC）。这些数据共同支持这样一种模型，即疟原虫 LS 招募宿主高尔基体形成 MT 介导的通道，沿这些通道招募宿主细胞器到 PVM 并支持寄生虫的发育。
