title: Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii.
abstract: Phosphoinositides regulate numerous cellular processes by recruiting cytosolic effector proteins and acting as membrane signalling entities. The cellular metabolism and localization of phosphoinositides are tightly regulated by distinct lipid kinases and phosphatases. Here, we identify and characterize a unique phosphatidylinositol 3 kinase (PI3K) in Toxoplasma gondii, a protozoan parasite belonging to the phylum Apicomplexa. Conditional depletion of this enzyme and subsequently of its product, PI(3)P, drastically alters the morphology and inheritance of the apicoplast, an endosymbiotic organelle of algal origin that is a unique feature of many Apicomplexa. We searched the T. gondii genome for PI(3)P-binding proteins and identified in total six PX and FYVE domain-containing proteins including a PIKfyve lipid kinase, which phosphorylates PI(3)P into PI(3,5)P2 . Although depletion of putative PI(3)P-binding proteins shows that they are not essential for parasite growth and apicoplast biology, conditional disruption of PIKfyve induces enlarged apicoplasts, as observed upon loss of PI(3)P. A similar defect of apicoplast homeostasis was also observed by knocking down the PIKfyve regulatory protein ArPIKfyve, suggesting that in T. gondii, PI(3)P-related function for the apicoplast might mainly be to serve as a precursor for the synthesis of PI(3,5)P2 . Accordingly, PI3K is conserved in all apicomplexan parasites whereas PIKfyve and ArPIKfyve are absent in Cryptosporidium species that lack an apicoplast, supporting a direct role of PI(3,5)P2 in apicoplast homeostasis. This study enriches the already diverse functions attributed to PI(3,5)P2 in eukaryotic cells and highlights these parasite lipid kinases as potential drug targets.
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, UMR5235 CNRS, Université de Montpellier 1 et 2, Montpellier, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: Daher
authors.forename: Juliette
authors.initials: J
authors.lastname: Morlon-Guyot
authors.forename: Lilach
authors.initials: L
authors.lastname: Sheiner
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Lentini
authors.forename: Laurence
authors.initials: L
authors.lastname: Berry
authors.forename: Lina
authors.initials: L
authors.lastname: Tawk
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dubremetz
authors.forename: Kai
authors.initials: K
authors.lastname: Wengelnik
authors.forename: Boris
authors.initials: B
authors.lastname: Striepen
authors.forename: Maryse
authors.initials: M
authors.lastname: Lebrun
mesh_terms: D063546:Apicoplasts / Q000378:metabolism* / Q000648:ultrastructure*; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D050356:Lipid Metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D058539:Phosphatidylinositol 3-Kinase