Phosphoinositide Metabolism Links cGMP-Dependent Protein Kinase G to Essential Ca2+ Signals at Key Decision Points in the Life Cycle of Malaria Parasites

Brochet, Mathieu; Collins, Mark O.; Smith, Terry; Thompson, Eloise; Sebastian, Sarah; Volkmann, Katrin; Schwach, Frank; Chappell, Lia; Gomes, Ana; Berriman, Matthew; Rayner, Julian C.; Baker, David A.; Choudhary, Jyoti S.; Billker, Oliver

doi:10.1371/journal.pbio.1001806

Cited by 204 publications

(319 citation statements)

References 62 publications

(107 reference statements)

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“…Zaprinast treatment also elevated cytosolic Ca 2ϩ in Toxoplasma similar to P. falciparum schizonts (19). In Toxoplasma, we found that the initial release of Ca 2ϩ from intracellular stores by zaprinast was largely independent of PKG activity but this increase in Ca 2ϩ was relatively short-lived suggesting that it is normally taken up or exported from the cell.…”

Section: Discussionmentioning

confidence: 49%

“…It is possible that the rapid PKG-independent pathway is due to release of Ca 2ϩ from cyclic nucleotidedependent calcium-release channels, or an off-target activity of the compound. In contrast, the PKG-dependent, prolonged duration of elevated Ca 2ϩ is reminiscent of the finding in P. berghei ookinetes and gametocytes, as well as P. falciparum schizonts, that PKG regulates phosphoinositide metabolism, leading to IP 3 -dependent Ca 2ϩ increases (19). Therefore in Toxoplasma, PKG may sustain cytosolic free Ca 2ϩ by maintaining IP 3 levels high via stimulating the production of and/or hydrolysis of PIP 2 .…”

Section: Discussionmentioning

confidence: 90%

“…Zaprinast has been shown to elevate Ca 2ϩ in P. falciparum schizonts (19), although the precise mechanism of this remains unknown. To determine whether this effect is also seen in Toxoplasma, we used time-resolved flow cytometric analysis of Ca 2ϩ levels in live RH-GCaMP6f parasites.…”

Section: Mic2-gluc-c-myc Is a Highly Sensitive Reporter Of Microneme mentioning

confidence: 99%

“…Together, it is thought that cGMP-mediated PKG activation and Ca 2ϩ -mediated CDPK activation control microneme secretion. There also may be significant cross-talk between these two signaling pathways because PKG has been shown to regulate calcium signaling by increasing phosphoinositol metabolism during gliding motility in Plasmodium berghei ookinetes, activation of P. berghei gametocytes, and egress of P. falciparum merozoites (19). Whether PKG has a similar function in other apicomplexans is currently not known.…”

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confidence: 99%

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Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii

Brown

Lourido

Sibley

2016

Journal of Biological Chemistry

103

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Microneme secretion is essential for motility, invasion, and egress in apicomplexan parasites. Although previous studies indicate that Ca 2؉ and cGMP control microneme secretion, little is known about how these pathways are naturally activated. Here we have developed genetically encoded indicators for Ca 2؉ and microneme secretion to better define the signaling pathways that regulate these processes in Toxoplasma gondii. We found that microneme secretion was triggered in vitro by exposure to a single host protein, serum albumin. The natural agonist serum albumin induced microneme secretion in a protein kinase G-dependent manner that correlated with increased cGMP levels. Surprisingly, serum albumin acted independently of elevated Ca 2؉ and yet it was augmented by artificial agonists that raise Ca 2؉ , such as ethanol. Furthermore, although ethanol elevated intracellular Ca 2؉ , it alone was unable to trigger secretion without the presence of serum or serum albumin. This dichotomy was recapitulated by zaprinast, a phosphodiesterase inhibitor that elevated cGMP and separately increased Ca 2؉ in a protein kinase G-independent manner leading to microneme secretion. Taken together, these findings reveal that microneme secretion is centrally controlled by protein kinase G and that this pathway is further augmented by elevation of intracellular Ca 2؉ .Toxoplasma gondii is an important opportunistic pathogen and model organism for studying the biology of members of the phylum Apicomplexa (1). Micronemes are specialized secretory vesicles present in all motile stages of apicomplexan parasites (reviewed in Ref. 2). The majority of internal microneme (MIC) 3 proteins (i.e. cargo) consist of adhesive proteins that translocate to the surface of the parasite following the regulated fusion of the organelle with the apical plasma membrane.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 90%

Section: Mic2-gluc-c-myc Is a Highly Sensitive Reporter Of Microneme mentioning

confidence: 99%

mentioning

confidence: 99%

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Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii

Brown

Lourido

Sibley

2016

Journal of Biological Chemistry

103

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“…Initially, a plasmodial guanylyl cyclase becomes activated, leading to the synthesis of cyclic GMP (cGMP) (Carucci et al, 2000;Muhia et al, 2001). The rise of cGMP activates the cGMP-dependent protein kinase G, which regulates the generation of PIP 2 (Alam et al, 2015;Brochet et al, 2014;McRobert et al, 2008). At the same time, PI-PLC is stimulated, which hydrolyses PIP 2 to generate DAG and IP 3 (Martin et al, 1994;Raabe et al, 2011b), resulting in the release of calcium from internal stores (Billker et al, 2004).…”

Section: The Role Of Plasmodial Phospholipases During Life-cycle Progmentioning

confidence: 99%

Phospholipases during membrane dynamics in malaria parasites

Flammersfeld

Lang

Flieger

et al. 2018

International Journal of Medical Microbiology

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A B S T R A C TPlasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.

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A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

Bullen

Soldati‐Favre

2016

FEBS Letters

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Edited by Wilhelm JustLipids are commonly known for the structural roles they play, however, the specific contribution of different lipid classes to wide-ranging signalling pathways is progressively being unravelled. Signalling lipids and their associated effector proteins are emerging as significant contributors to a vast array of effector functions within cells, including essential processes such as membrane fusion and vesicle exocytosis. Many phospholipids have signalling capacity, however, this review will focus on phosphatidic acid (PA) and the enzymes implicated in its production from diacylglycerol (DAG) and phosphatidylcholine (PC): DGK and PLD respectively. PA is a negatively charged, coneshaped lipid identified as a key mediator in specific membrane fusion and vesicle exocytosis events in a variety of mammalian cells, and has recently been implicated in specialised secretory organelle exocytosis in apicomplexan parasites. This review summarises the recent work implicating a role for PA regulation in exocytosis in various cell types. We will discuss how these signalling events are linked to pathogenesis in the phylum Apicomplexa.

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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

Abstract: Chemical genetics and a global comparative analysis of phosphorylation and phospholipids in vivo shows that PKG is the upstream regulator that induces calcium signals that enables Plasmodium to progress through its complex life cycle.

Cited by 204 publications

References 62 publications

Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii

Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii

Phospholipases during membrane dynamics in malaria parasites

A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

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