A role for coccidian cGMP-dependent protein kinase in motility and invasion

Wiersma, Helen I; Galuska, Stefan; Tomley, Fiona M.; Sibley, L. David; Liberator, Paul; Donald, Robert G. K.

doi:10.1016/j.ijpara.2003.11.019

Cited by 131 publications

(132 citation statements)

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“…TgCDPK3 also contributes to microneme secretion in some conditions and is important for regulating egress (9 -11). Notably, activation of Toxoplasma cyclic GMP-dependent protein kinase (TgPKG), which is also required for invasion (15) and egress, can compensate for the role of TgCDPK3 (9). Consistent with this finding, cyclic GMP (cGMP) has emerged as a second signaling molecule that stimulates microneme secretion.…”

mentioning

confidence: 83%

“…The Role of Cyclic GMP and PKG on Stimulated Microneme Secretion-Previous studies have shown that PKG is required for Toxoplasma microneme secretion and microneme-dependent cellular processes (15,18,37,38). Because PKG is activated by the second messenger cGMP, compounds that elevate cGMP levels should stimulate microneme secretion.…”

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

confidence: 99%

“…Indirect evidence for this pathway is provided by inhibitors of cGMP-specific phosphodiesterases (PDE), such as zaprinast and BIPPO, which stimulate microneme secretion and egress in Toxoplasma (9,16), and Plasmodium falciparum merozoites (17). More directly, chemical-genetic studies showed that inhibition of PKG blocks microneme secretion in Eimeria tenella sporozoites (15), Toxoplasma tachyzoites (15), and P. falciparum merozoites (17). These studies relied on a specific inhibitor called Compound 1 that inhibits the wild-type enzyme, which has a Thr gatekeeper, whereas mutation of this residue to Met/ Gln results in resistance (18).…”

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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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confidence: 83%

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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“…Inhibition of the T. gondii cGMP-dependent protein kinase G (PKG) by compound 1 was also found to inhibit microneme discharge with a minimal effect on intracellular parasite growth (Wiersma et al, 2004). Moreover, the PKG locus was proved to be refractory to gene disruption, suggesting a vital function (Donald et al, 2002).…”

Section: Microneme Secretion and Egressmentioning

confidence: 99%

“…In fact, many of the processes controlled by cGMP appear to be also regulated by calcium, and hence the two pathways are likely interconnected (Hopp et al, 2012). In T. gondii, PKG is believed to act downstream of calcium, as calcium ionophores are not able to induce microneme secretion in parasites treated with PKG inhibitors (Wiersma et al, 2004). In Plasmodium spp., the picture is more complicated due to the multiple effects resulting from PKG inhibition.…”

Section: Microneme Secretion and Egressmentioning

confidence: 99%

Does protein phosphorylation govern host cell entry and egress by the Apicomplexa?

Jacot

Soldati‐Favre

2012

International Journal of Medical Microbiology

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a b s t r a c tMembers of the phylum Apicomplexa are responsible for a wide range of diseases in humans and animals. The absence of an effective vaccine or safe curing drugs and the continuous emergence of resistant parasites to available treatments impose a high demand on the identification of novel targets for intervention against the apicomplexans. Protein kinases are considered attractive potential therapeutic targets not only against cancers but also to combat infectious diseases. The scope and aim of this review is to report on the recent progress in dissecting the impact of protein phosphorylation in regulating motility and invasion.

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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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A role for coccidian cGMP-dependent protein kinase in motility and invasion

Cited by 131 publications

References 49 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

Does protein phosphorylation govern host cell entry and egress by the Apicomplexa?

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

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