Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites

This work was funded by grants from the Wellcome Trust (WT098051 and 079643/Z/06/Z) and the Medical Research Council (G0501670) to OB, a Wellcome Trust project grant to DB (WT094752), a Wellcome Trust Grant (WT093228) to TKS, a Marie Curie Fellowship (PIEF-GA-2008-220180) to SS, and a Marie Curie Fellowship (PIEF-GA-2009-253899) and an EMBO Long Term Fellowship (ALTF 45-2009) to MBr. C2 was synthesised and kindly provided by Katy Kettleborough and colleagues at MRC Technology through an MRC grant to DB (G10000779).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.Publisher PDFPeer reviewe

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