Two phylogenetically and compartmentally distinct CDP-diacylglycerol synthases cooperate for lipid biogenesis inToxoplasma gondii.
Toxoplasma gondiiis among the most prevalent protozoan parasites, which infects a wide range of organisms, including one-third of the human population. Its rapid intracellular replication within a vacuole requires efficient synthesis of glycerophospholipids. Cytidine diphosphate-diacylglycerol (CDP-DAG) serves as a major precursor for phospholipid synthesis. Given the peculiarities of lipid biogenesis, understanding the mechanism and physiological importance of CDP-DAG synthesis is particularly relevant inT. gondiiHere, we report the occurrence of two phylogenetically divergent CDP-DAG synthase (CDS) enzymes in the parasite. The eukaryotic-typeTgCDS1 and the prokaryotic-typeTgCDS2 reside in the endoplasmic reticulum and apicoplast, respectively. Conditional knockdown ofTgCDS1 severely attenuated the parasite growth and resulted in a nearly complete loss of virulence in a mouse model. Moreover, mice infected with theTgCDS1 mutant became fully resistant to challenge infection with a hyper-virulent strain ofT. gondiiThe residual growth of theTgCDS1 mutant was abolished by consecutive deletion ofTgCDS2. Lipidomic analyses of the two mutants revealed significant and specific declines in phosphatidylinositol and phosphatidylglycerol levels upon repression ofTgCDS1 and after deletion ofTgCDS2, respectively. Our data suggest a "division of labor" model of lipid biogenesis inT. gondiiin which two discrete CDP-DAG pools produced in the endoplasmic reticulum and apicoplast are subsequently used for the synthesis of phosphatidylinositol in the Golgi bodies and phosphatidylglycerol in the mitochondria. The essential and divergent nature of CDP-DAG synthesis in the parasite apicoplast offers a potential drug target to inhibit the asexual reproduction ofT. gondii.
From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany.
Pengfei
0000-0003-2944-5874
P
Kong
From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany.
Christoph-Martin
CM
Ufermann
From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany.
Diana L M
DLM
Zimmermann
National Animal Protozoa Laboratory and College of Veterinary Medicine, China Agricultural University, Beijing 100094, China, and.
Qing
Q
Yin
National Animal Protozoa Laboratory and College of Veterinary Medicine, China Agricultural University, Beijing 100094, China, and.
Xun
X
Suo
Department of Biochemistry and Cell Biology, Institute of Biomembranes, Utrecht University, Utrecht 3584CM, Netherlands.
J Bernd
JB
Helms
Department of Biochemistry and Cell Biology, Institute of Biomembranes, Utrecht University, Utrecht 3584CM, Netherlands.
Jos F
JF
Brouwers
From the Department of Molecular Parasitology, Humboldt University, Berlin 10115, Germany, Gupta.Nishith@staff.hu-berlin.de.
Nishith
0000-0003-1452-5126
N
Gupta
D000818:Animals; D030801:Animals, Genetically Modified; D063546:Apicoplasts / Q000201:enzymology; D002798:Diacylglycerol Cholinephosphotransferase / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D020404:Glycerophospholipids / Q000096:biosynthesis*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010715:Phosphatidylglycerols / Q000737:chemistry; D010716:Phosphatidylinositols / Q000737:chemistry; D010802:Phylogeny; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D014122:Toxoplasma / Q000201:enzymology* / Q000235:genetics; D014774:Virulence
D020404:Glycerophospholipids; D010715:Phosphatidylglycerols; D010716:Phosphatidylinositols; D015800:Protozoan Proteins; D002798:Diacylglycerol Cholinephosphotransferase
Toxoplasma gondii; glycerophospholipid; parasite metabolism; phosphatidylglycerol; phosphatidylinositol