title: Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.
abstract: Many critical events in the Plasmodium life cycle rely on the controlled release of Ca²⁺ from intracellular stores to activate stage-specific Ca²⁺-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca²⁺ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5)-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca²⁺ effectors, PKG emerges as a unifying factor to control multiple cellular Ca²⁺ signals essential for malaria parasite development and transmission.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Brochet
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Collins
authors.affiliation: Schools of Biology and Chemistry, Biomedical Sciences Research Complex, The North Haugh, The University of Saint Andrews, St. Andrews, Fife United Kingdom.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Eloise
authors.initials: E
authors.lastname: Thompson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sebastian
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Katrin
authors.initials: K
authors.lastname: Volkmann
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Schwach
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Lia
authors.initials: L
authors.lastname: Chappell
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Berriman
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Choudhary
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D009033:Culicidae / Q000469:parasitology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D006790:Host-Parasite Interactions; D006801:Humans; D008018:Life Cycle Stages; D008288:Malaria / Q000469:parasitology; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*
chemical_list: D010716:Phosphatidylinositols; D017869:Cyclic GMP-Dependent Protein Kinases