Phosphatidic acid governs natural egress in Toxoplasma gondii via a guanylate cyclase receptor platform

Bisio, Hugo; Lunghi, Matteo; Brochet, Mathieu; Soldati‐Favre, Dominique

doi:10.1038/s41564-018-0339-8

Cited by 106 publications

(195 citation statements)

References 40 publications

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“…TgGC is the only flippase, (lipid transporters that flip lipids across membranes) and an unusual Alveolate-specific dual domain flippase-guanylate cyclase fusion protein (Figure S1). Previous studies all showed that TgGC is primarily found at the apical cap (Yang et al 2019;Brown and Sibley 2018;Bisio et al 2019), but it is also present in other secondary locations including an ER-like compartment (Brown and Sibley 2018), and the residual body (Bisio et al 2019). This mixed distribution is consistent with a recent hyperLOPIT (Localization of Organellar Proteins by Isotopic Tagging) study that did not assign TgGC to any one location although did indicate a dynamic distribution including the Golgi (Barylyuk et al, n.d.) (www.toxodb.org).…”

Section: Tggc Has a Dynamic Localizationsupporting

confidence: 79%

“…Instead, apicomplexans possess an unusual alveolate-specific dual-domain phospholipid transporter/cGMP cyclase protein (TgGC) fusion protein (Johnson and Leroux 2010;Yang et al 2019). Recently in Toxoplasma, TgGC has been shown to be critical for activation of TgPKG to trigger microneme secretion (Brown and Sibley 2018;Yang et al 2019;Bisio et al 2019). Similarly, Plasmodium species possess two GCs, type a and type b (GCa + GCb), and the Plasmodium yoelli protein PyGCb has been shown to have an apical localization in sporozoites, critical for ookinete traversal of the mosquito midgut (Gao et al 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The function of the P-Type ATPase domain of TgGC is poorly understood but is predicted to have a role in lipid trafficking across membranes, or possibly of ion transport such as K + or Ca 2+ (Yang et al 2019;Bisio et al 2019). However, several studies have concluded that both domains are essential for TgGC function and that the ATPase domain likely links a metabolic function to a signalling response (Brown and Sibley 2018;Yang et al 2019), although extensive lipidomic analysis in TgGC-depleted cells is lacking.…”

Section: Introductionmentioning

confidence: 99%

“…However, several studies have concluded that both domains are essential for TgGC function and that the ATPase domain likely links a metabolic function to a signalling response (Brown and Sibley 2018;Yang et al 2019), although extensive lipidomic analysis in TgGC-depleted cells is lacking. Exactly what the substrate of the ATPase domain might be is uncertain although it has been shown that cells with disrupted TgGC are less responsive to changes in pH while disruption of cofactors of TgGC, including TgCDC50, leads to parasites that can still egress in response to changes in pH (Bisio et al 2019), suggesting that TgGC is the primary responder to external pH signals. This change in pH is thought to be mediated at least in part by phosphatidic acid (Bisio et al 2019), which due to its sole phosphate headgroup can bear variable charge through variable binding of hydrogen groups from the external environment (Abramson et al 1964;van Paridon et al 1986).…”

Section: Introductionmentioning

confidence: 99%

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Rapid kinetics of lipid second messengers controlled by a cGMP signalling network coordinates apical complex functions inToxoplasmatachyzoites

Katris

Yamaryo‐Botté

Janouškovec

et al. 2020

Preprint

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Host cell invasion and subsequent egress by Toxoplasma parasites is regulated by a network of cGMP, cAMP, and calcium signalling proteins. Such eukaryotic signalling networks typically involve lipid second messengers including phosphatidylinositol phosphates (PIPs), diacylglycerol (DAG) and phosphatidic acid (PA). However, the lipid signalling network in Toxoplasma is poorly defined. Here we present lipidomic analysis of a mutant of central flippase/guanylate cyclase TgGC in Toxoplasma, which we show has disrupted turnover of signalling lipids impacting phospholipid metabolism and membrane stability. The turnover of signalling lipids is extremely rapid in extracellular parasites and we track changes in PA and DAG to within 5 seconds, which are variably defective upon disruption of TgGC and other signalling proteins. We then identify the position of each protein in the signal chain relative to the central cGMP signalling protein TgGC and map the lipid signal network coordinating conoid extrusion and microneme secretion for egress and invasion.

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Section: Tggc Has a Dynamic Localizationsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rapid kinetics of lipid second messengers controlled by a cGMP signalling network coordinates apical complex functions inToxoplasmatachyzoites

Katris

Yamaryo‐Botté

Janouškovec

et al. 2020

Preprint

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“…Within host cells parasites are stationary, non-motile, and surrounded by low Ca 2+ , yet activation by an intrinsic signal like phosphatidic acid as recently proposed [49], would start a signaling cascade leading to a rise in cytosolic Ca 2+ followed by stimulation of motility.…”

Section: Discussionmentioning

confidence: 95%

The Role of Potassium and Host Calcium Signaling inToxoplasma gondiiegress

Vella

Moore

et al. 2020

Preprint

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Toxoplasma gondii, an obligate intracellular parasite, is capable of invading virtually any nucleated cell. Active invasion by the parasite is a precise process and intracellular parasites reside and replicate inside a parasitophorous vacuole (PV). The membrane of the PV functions as a molecular sieve allowing for its ionic milieu to be in equilibrium with the host cytosol. The parasite would thus be exposed to the ionic fluctuations of the host cytoplasm, such as increases in host cytosolic Ca 2+ during Ca 2+ signaling events. Ca 2+ is a universal signaling molecule and both the host cell and T. gondii will utilize Ca 2+ signaling to stimulate diverse cellular functions. Using T. gondii tachyzoites and host cells expressing genetically encoded Ca 2+ indicators, we demonstrate that host Ca 2+ signaling impacts intracellular Ca 2+ levels of the parasite. We propose that Ca 2+ influx derived from host Ca 2+ signaling into the parasite is utilized to maintain the intracellular Ca 2+ stores replenished as the parasite replicates within the low Ca 2+ environment of the host cell.Intracellular Ca 2+ store(s) release is needed to reach the initiation spike in Ca 2+ that meets the threshold of Ca 2+ needed to initiate the tightly coordinated process of egress. Post activation of the signal and subsequent microneme secretion, would cause breakdown of the host cell and allow for extracellular Ca 2+ influx, causing a second, larger spike in Ca 2+ and activation of the glideosome, the main motility machinery. To directly deliver precise concentrations of ions needed for egress, we used patch-clamped infected host cells and monitored parasite egress. In doing so, we discovered an alternative role for K + in timing parasite egress. This is the first study using wholecell patch clamp to study the role of ions such as K + and Ca 2+ in T. gondii egress. Author SummaryToxoplasma gondii is an intracellular parasite that causes disease by engaging in multiple rounds of a lytic cycle which consists of invasion, replication inside a parasitophorous vacuole (PV) and egress, resulting in lysis of the host cell. In intracellular parasites, the release of Ca 2+ from intracellular stores forms part of a series of signaling events that culminate in stimulation of motility and egress. This means that intracellular parasites must be able to uptake Ca 2+ while replicating to keep their intracellular stores filled to be used during egress. This is not an insignificant task considering that they are inside a PV surrounded by the host cytosol which contains Ca 2+ below 100 nM. We present data showing that the host Ca 2+ increases are able to 3 reach the parasite cytosol through a Ca 2+ influx mechanism sensitive to nifedipine. This influx causes oscillations that are the result of Ca 2+ increase and re-uptake by intracellular stores. A Ca 2+ threshold was needed for egress, extracellular Ca 2+ influx was relevant for egress and potassium had a modulatory effect on egress. We used infected patched host cells, a novel approach that leaves the host ...

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cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

Friebe

Sandner

Schmidtko

2019

Naunyn-Schmiedeberg's Arch Pharmacol

101

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Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC-and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the "9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications" held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

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Phosphatidic acid governs natural egress in Toxoplasma gondii via a guanylate cyclase receptor platform

Cited by 106 publications

References 40 publications

Rapid kinetics of lipid second messengers controlled by a cGMP signalling network coordinates apical complex functions inToxoplasmatachyzoites

Rapid kinetics of lipid second messengers controlled by a cGMP signalling network coordinates apical complex functions inToxoplasmatachyzoites

The Role of Potassium and Host Calcium Signaling inToxoplasma gondiiegress

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

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