一种细胞内膜蛋白 GEP1 调控黄尿酸诱导的疟原虫配子发生。
An intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites.
机构信息
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102, Xiamen, Fujian, China.
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
出版信息
Nat Commun. 2020 Apr 9;11(1):1764. doi: 10.1038/s41467-020-15479-3.
Gametocytes differentiation to gametes (gametogenesis) within mosquitos is essential for malaria parasite transmission. Both reduction in temperature and mosquito-derived XA or elevated pH are required for triggering cGMP/PKG dependent gametogenesis. However, the parasite molecule for sensing or transducing these environmental signals to initiate gametogenesis remains unknown. Here we perform a CRISPR/Cas9-based functional screening of 59 membrane proteins expressed in the gametocytes of Plasmodium yoelii and identify that GEP1 is required for XA-stimulated gametogenesis. GEP1 disruption abolishes XA-stimulated cGMP synthesis and the subsequent signaling and cellular events, such as Ca mobilization, gamete formation, and gametes egress out of erythrocytes. GEP1 interacts with GCα, a cGMP synthesizing enzyme in gametocytes. Both GEP1 and GCα are expressed in cytoplasmic puncta of both male and female gametocytes. Depletion of GCα impairs XA-stimulated gametogenesis, mimicking the defect of GEP1 disruption. The identification of GEP1 being essential for gametogenesis provides a potential new target for intervention of parasite transmission.
疟原虫配子体分化为配子（配子发生）是疟疾寄生虫传播所必需的。温度降低和蚊源 XA 或 pH 值升高都需要触发 cGMP/PKG 依赖性配子发生。然而，用于感知或转导这些环境信号以启动配子发生的寄生虫分子仍然未知。在这里，我们对 Plasmodium yoelii 配子体中表达的 59 种膜蛋白进行了基于 CRISPR/Cas9 的功能筛选，鉴定出 GEP1 是 XA 刺激配子发生所必需的。GEP1 缺失会破坏 XA 刺激的 cGMP 合成以及随后的信号和细胞事件，例如 Ca 动员、配子形成和配子从红细胞中逸出。GEP1 与 GCα 相互作用，GCα 是配子体中的 cGMP 合成酶。GEP1 和 GCα 都在雄性和雌性配子体的细胞质斑点中表达。GCα 的耗竭会损害 XA 刺激的配子发生，类似于 GEP1 缺失的缺陷。GEP1 对配子发生至关重要的鉴定为寄生虫传播的干预提供了一个潜在的新靶点。
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