该工作历时四年，由博士毕业生高涵（第一作者）、博士生杨振科和王旭（共同第一作者）、硕士生钱鹏戈和洪仁杰完成；袁晶教授为通讯作者；厦门大学为第一完成单位。
该工作揭示了疟疾病原疟原虫通过媒介按蚊传播过程中的关键步骤---控制动合子运动的环磷酸鸟苷cGMP信号的激活机制。
疟原虫属于顶复体亚门原生动物，每年导致数亿人口感染疟疾和超过40万病人死亡。疟原虫通过雌性按蚊在哺乳动物宿主间传播。疟疾病人被按蚊叮咬吸血，疟原虫雌雄配子在按蚊消化道中受精形成合子，进一步变形发育为具有运动能力的新月形动合子。只有获得运动能力的动合子，才能穿越按蚊消化道单层上皮细胞，成功感染按蚊媒介。在本研究中，通过大量基因修饰模型，发现GCβ缺失导致动合子运动完全丢失，进而失去按蚊感染和传播能力。研究还发现，GCβ由细胞质均匀分布改变为在动合子顶体突出一侧聚集，并且GCβ聚集和动合子成熟完全同步，显示GCβ聚集可能直接激活cGMP信号。
本工作还发现GCβ结合蛋白CDC50A，后者承担分子伴侣功能，在动合子转化和成熟动合子中，稳定GCβ。此外，进一步筛选发现动合子内膜复合物蛋白ISP1，能够结合和锚定GCβ/CDC50A复合物，在成熟动合子中维持复合物的聚集。本研究为深入开展寄生性原生动物的发育转化和信号调控提供了线索和借鉴。【Abstract】Ookinete gliding motility is essential for penetration of the mosquito midgut wall and transmission of malaria parasites. Cyclic guanosine monophosphate (cGMP) signaling has been implicated in ookinete gliding. However, the upstream mechanism of how the parasites activate cGMP signaling and thus initiate ookinete gliding remains unknown. Using real-time imaging to visualize Plasmodium yoelii guanylate cyclase β (GCβ), we show that cytoplasmic GCβ translocates and polarizes to the parasite plasma membrane at “ookinete extrados site” (OES) during zygote to ookinete differentiation. The polarization of enzymatic active GCβ at OES initiates gliding of matured ookinete. Both the P4-ATPase-like domain and guanylate cyclase domain are required for GCβ polarization and ookinete gliding. CDC50A, a co-factor of P4-ATPase, binds to and stabilizes GCβ during ookinete development. Screening of inner membrane complex proteins identifies ISP1 as a key molecule that anchors GCβ/CDC50A complex at the OES of mature ookinetes. This study defines a spatial-temporal mechanism for the initiation of ookinete gliding, where GCβ polarization likely elevates local cGMP levels and activates cGMP-dependent protein kinase signaling.We thank Dr. David Baker (London School of Hygiene and Tropical Medicine) for his comments on this manuscript. This work was supported by the National Natural Science Foundation of China (81522027, 31772443, and 31501912), the Fundamental Research Funds for the Central Universities (20720160069, 20720150165, and 2013121033), the China's 1000 Young Talents Program, the “111” Project of the Ministration of Education of China (B06016), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH (X.S.). The authors thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance.
该研究得到国家自然科学基金委、中组部“青年千人计划”和厦门大学校长基金的资助
