Toxoplasma gondii phosphatidylserine flippase complex ATP2B-CDC50.4 critically participates in microneme exocytosis

Author summaryBiological membranes display diverse functions, including membrane fusion, which are conferred by a defined composition and organization of proteins and lipids. Apicomplexan parasites possess specialized secretory organelles (micronemes), implicated in motility, invasion and egress from host cells. Microneme exocytosis is already known to depend on phosphatidic acid for its fusion with the plasma membrane. Here we identify a type P4-ATPase and its CDC50 chaperone (ATP2B-CDC50.4) that act as a flippase and contribute to the enrichment of phosphatidylserine (PS) in the inner leaflet of the parasite plasma membrane. The disruption of PS asymmetric distribution at the plasma membrane impacts microneme exocytosis. Overall, our results shed light on the importance of membrane homeostasis and lipid composition in controlling microneme secretion. Regulated microneme secretion governs motility, host cell invasion and egress in the obligate intracellular apicomplexans. Intracellular calcium oscillations and phospholipid dynamics critically regulate microneme exocytosis. Despite its importance for the lytic cycle of these parasites, molecular mechanistic details about exocytosis are still missing. Some members of the P4-ATPases act as flippases, changing the phospholipid distribution by translocation from the outer to the inner leaflet of the membrane. Here, the localization and function of the repertoire of P4-ATPases was investigated across the lytic cycle of Toxoplasma gondii. Of relevance, ATP2B and the non-catalytic subunit cell division control protein 50.4 (CDC50.4) form a stable heterocomplex at the parasite plasma membrane, essential for microneme exocytosis. This complex is responsible for flipping phosphatidylserine, which presumably acts as a lipid mediator for organelle fusion with the plasma membrane. Overall, this study points toward the importance of phosphatidylserine asymmetric distribution at the plasma membrane for microneme exocytosis.

Automated summary

This study identifies the role of a type P4-ATPase and its chaperone CDC50 in regulating microneme exocytosis in apicomplexan parasites. The researchers found that this protein complex is responsible for maintaining the asymmetric distribution of phosphatidylserine in the parasite plasma membrane, which is crucial for microneme fusion with the plasma membrane. These findings highlight the importance of membrane homeostasis and lipid composition in controlling microneme secretion.