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

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Date
04/03/2014
Author
Brochet, Mathieu
Collins, Mark O.
Smith, Terry K.
Thompson, Eloise
Sebastian, Sarah
Volkmann, Katrin
Schwach, Frank
Chappell, Lia
Gomes, Ana Rita
Berriman, Matthew
Rayner, Julian C.
Baker, David A.
Choudhary, Jyoti
Billker, Oliver
Funder
The Wellcome Trust
Grant ID
093228/Z/10/Z
Keywords
Plasmodium-falciparum
Guanylyl cyclase
Sample preparation
Xanthurenic acid
RNA-SEQ
In-vivo
Calcium
Berghei
Cell
Mosquito
QH301 Biology
BDC
R2C
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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.
Citation
Brochet , M , Collins , M O , Smith , T K , Thompson , E , Sebastian , S , Volkmann , K , Schwach , F , Chappell , L , Gomes , A R , Berriman , M , Rayner , J C , Baker , D A , Choudhary , J & Billker , O 2014 , ' Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites ' , PLoS Biology , vol. 12 , no. 3 , e1001806 . https://doi.org/10.1371/journal.pbio.1001806
Publication
PLoS Biology
Status
Peer reviewed
DOI
https://doi.org/10.1371/journal.pbio.1001806
ISSN
1545-7885
Type
Journal article
Rights
Copyright © 2014 Brochet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description
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).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/4709

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