Toxoplasma Gondii Phosphatidylserine Flippase Complex ATP2B-CDC50.4 Critically Participates in Microneme Exocytosis

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2022 Mar 24

PMID 35325010

Authors

Hugo Bisio

Aarti Krishnan

Jean-Baptiste Marq

Dominique Soldati-Favre

Affiliations

Soon will be listed here.

Abstract

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.

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References

Sudhof T, Rizo J . Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol. 2011; 3(12). PMC: 3225952. DOI: 10.1101/cshperspect.a005637. View

Huang B, Akbar M, Kevala K, Kim H . Phosphatidylserine is a critical modulator for Akt activation. J Cell Biol. 2011; 192(6):979-92. PMC: 3063130. DOI: 10.1083/jcb.201005100. View

Linder J, Hoffmann T, Kurz U, Schultz J . A guanylyl cyclase from Paramecium with 22 transmembrane spans. Expression of the catalytic domains and formation of chimeras with the catalytic domains of mammalian adenylyl cyclases. J Biol Chem. 2001; 275(15):11235-40. DOI: 10.1074/jbc.275.15.11235. View

Daleke D . Phospholipid flippases. J Biol Chem. 2006; 282(2):821-5. DOI: 10.1074/jbc.R600035200. View

Edgar R . MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics. 2004; 5:113. PMC: 517706. DOI: 10.1186/1471-2105-5-113. View

DaMatta R, Seabra S, Deolindo P, Arnholdt A, Manhaes L, Goldenberg S . Trypanosoma cruzi exposes phosphatidylserine as an evasion mechanism. FEMS Microbiol Lett. 2006; 266(1):29-33. DOI: 10.1111/j.1574-6968.2006.00495.x. View

Shao C, Novakovic V, Head J, Seaton B, Gilbert G . Crystal structure of lactadherin C2 domain at 1.7A resolution with mutational and computational analyses of its membrane-binding motif. J Biol Chem. 2007; 283(11):7230-41. DOI: 10.1074/jbc.M705195200. View

Sidik S, Huet D, Ganesan S, Huynh M, Wang T, Nasamu A . A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes. Cell. 2016; 166(6):1423-1435.e12. PMC: 5017925. DOI: 10.1016/j.cell.2016.08.019. View

Dos Santos T, de Araujo Portes J, Damasceno-Sa J, Caldas L, De Souza W, DaMatta R . Phosphatidylserine exposure by Toxoplasma gondii is fundamental to balance the immune response granting survival of the parasite and of the host. PLoS One. 2011; 6(11):e27867. PMC: 3226563. DOI: 10.1371/journal.pone.0027867. View

10.

Gurtovenko A, Vattulainen I . Membrane potential and electrostatics of phospholipid bilayers with asymmetric transmembrane distribution of anionic lipids. J Phys Chem B. 2008; 112(15):4629-34. DOI: 10.1021/jp8001993. View

11.

Wang S, Li Y, Ma C . Synaptotagmin-1 C2B domain interacts simultaneously with SNAREs and membranes to promote membrane fusion. Elife. 2016; 5. PMC: 4878868. DOI: 10.7554/eLife.14211. View

12.

Jiang Y, Wei J, Cui H, Liu C, Zhi Y, Jiang Z . An intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites. Nat Commun. 2020; 11(1):1764. PMC: 7145802. DOI: 10.1038/s41467-020-15479-3. View

13.

Uboldi A, Wilde M, McRae E, Stewart R, Dagley L, Yang L . Protein kinase A negatively regulates Ca2+ signalling in Toxoplasma gondii. PLoS Biol. 2018; 16(9):e2005642. PMC: 6152992. DOI: 10.1371/journal.pbio.2005642. View

14.

Kim K, Soldati D, Boothroyd J . Gene replacement in Toxoplasma gondii with chloramphenicol acetyltransferase as selectable marker. Science. 1993; 262(5135):911-4. DOI: 10.1126/science.8235614. View

15.

Tanaka Y, Ono N, Shima T, Tanaka G, Katoh Y, Nakayama K . The phospholipid flippase ATP9A is required for the recycling pathway from the endosomes to the plasma membrane. Mol Biol Cell. 2016; 27(24):3883-3893. PMC: 5170610. DOI: 10.1091/mbc.E16-08-0586. View

16.

Wicky S, Schwarz H, Singer-Kruger B . Molecular interactions of yeast Neo1p, an essential member of the Drs2 family of aminophospholipid translocases, and its role in membrane trafficking within the endomembrane system. Mol Cell Biol. 2004; 24(17):7402-18. PMC: 507011. DOI: 10.1128/MCB.24.17.7402-7418.2004. View

17.

Chen K, Gunay-Esiyok O, Klingeberg M, Marquardt S, Pomorski T, Gupta N . Aminoglycerophospholipid flipping and P4-ATPases in Toxoplasma gondii. J Biol Chem. 2021; 296:100315. PMC: 7949121. DOI: 10.1016/j.jbc.2021.100315. View

18.

Morrison W . Progress towards understanding the immunobiology of Theileria parasites. Parasitology. 2009; 136(12):1415-26. DOI: 10.1017/S0031182009990916. View

19.

Kenthirapalan S, Waters A, Matuschewski K, Kooij T . Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite. Nat Commun. 2016; 7:10519. PMC: 4736113. DOI: 10.1038/ncomms10519. View

20.

Gao H, Yang Z, Wang X, Qian P, Hong R, Chen X . ISP1-Anchored Polarization of GCβ/CDC50A Complex Initiates Malaria Ookinete Gliding Motility. Curr Biol. 2018; 28(17):2763-2776.e6. DOI: 10.1016/j.cub.2018.06.069. View