Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1 Rue Michel Servet, 12111 Geneva, Switzerland.
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland.
Sci Adv. 2023 Jun 16;9(24):eadf2161. doi: 10.1126/sciadv.adf2161.
Critical events in the life cycle of malaria-causing parasites depend on cyclic guanosine monophosphate homeostasis by guanylyl cyclases (GCs) and phosphodiesterases, including merozoite egress or invasion of erythrocytes and gametocyte activation. These processes rely on a single GCα, but in the absence of known signaling receptors, how this pathway integrates distinct triggers is unknown. We show that temperature-dependent epistatic interactions between phosphodiesterases counterbalance GCα basal activity preventing gametocyte activation before mosquito blood feed. GCα interacts with two multipass membrane cofactors in schizonts and gametocytes: UGO (unique GC organizer) and SLF (signaling linking factor). While SLF regulates GCα basal activity, UGO is essential for GCα up-regulation in response to natural signals inducing merozoite egress and gametocyte activation. This work identifies a GC membrane receptor platform that senses signals triggering processes specific to an intracellular parasitic lifestyle, including host cell egress and invasion to ensure intraerythrocytic amplification and transmission to mosquitoes.
疟原虫生命周期中的关键事件依赖于鸟苷酸环化酶（GCs）和磷酸二酯酶（PDEs）的环鸟苷单磷酸（cGMP）稳态，包括裂殖子出芽或红细胞入侵和配子体激活。这些过程依赖于单个 GCα，但在缺乏已知信号受体的情况下，该途径如何整合不同的触发因素尚不清楚。我们表明，在蚊子吸血之前，磷酸二酯酶之间温度依赖性的上位相互作用平衡 GCα 的基础活性，从而防止配子体激活。GCα 在裂殖体和配子体中与两个多跨膜共因子相互作用：UGO（独特 GC 组织者）和 SLF（信号连接因子）。虽然 SLF 调节 GCα 的基础活性，但 UGO 对于 GCα 的上调是必需的，以响应自然信号诱导裂殖子出芽和配子体激活。这项工作确定了一个 GC 膜受体平台，它可以感知触发特定于细胞内寄生生活方式的信号，包括宿主细胞出芽和入侵，以确保在红细胞内扩增和传播到蚊子。
