Calcium and cyclic nucleotide signaling networks in Toxoplasma gondii

Brown, Kevin M.; Tonkin, Christopher J.; Billker, Oliver; Sibley, L. David

doi:10.1016/b978-0-12-815041-2.00013-x

Cited by 8 publications

(6 citation statements)

References 149 publications

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“…We can emulate the endogenous signaling pathways that mediate the kinetic phase of the lytic cycle by treating isolated parasites with zaprinast, which stimulates PKG activation by inhibiting phosphodiesterases that degrade cGMP ( Brown et al, 2016 ; Lourido et al, 2012 ). Zaprinast-stimulated motility occurs rapidly and in defined sequence in apicomplexans: initially, an increase in cGMP activates parasite protein kinase G (PKG), which phosphorylates substrates and stimulates Ca 2+ release from internal stores ( Brown et al, 2020 ; Lourido and Moreno, 2015 ). PKG likely performs functions that extend beyond regulating Ca 2+ stores, for example by mobilizing diacylglycerol and phosphatidic acid ( Lourido et al, 2012 ; Brown et al, 2017 ; Bullen et al, 2016 ; Bisio et al, 2019 ); however, the use or phosphodiesterase inhibitors like zaprinast allows us to stimulate endogenous Ca 2+ release without flooding the cell with Ca 2+ , as is the case with ionophores.…”

Section: Resultsmentioning

confidence: 99%

“…Apicomplexan signaling pathways have largely been characterized through a combination of genetic manipulation, pharmacological perturbation, and physiological observation ( Bisio and Soldati-Favre, 2019 ; Brown et al, 2020 ; Lourido and Moreno, 2015 ). Such approaches have been sufficient to document feedback loops between cyclic nucleotide signaling and Ca 2+ -store release and influx.…”

Section: Discussionmentioning

confidence: 99%

“…Ca 2+ signaling pathways have been repurposed in apicomplexans to regulate parasite-specific cellular processes governing the transition between the replicative and kinetic phases of the infectious cycle ( Brown et al, 2020 ; Pace et al, 2020 ). Despite the presence of conserved Ca 2+ -responsive proteins ( Lourido and Moreno, 2015 ; Nagamune and Sibley, 2006 ), uncovering the Ca 2+ signaling architecture of apicomplexans demands a reevaluation of the entire network to understand how specific signaling elements interact to impact pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways

Herneisen

Chan

et al. 2022

eLife

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Apicomplexan parasites cause persistent mortality and morbidity worldwide through diseases including malaria, toxoplasmosis, and cryptosporidiosis. Ca2+ signaling pathways have been repurposed in these eukaryotic pathogens to regulate parasite-specific cellular processes governing the replicative and lytic phases of the infectious cycle, as well as the transition between them. Despite the presence of conserved Ca2+-responsive proteins, little is known about how specific signaling elements interact to impact pathogenesis. We mapped the Ca2+-responsive proteome of the model apicomplexan T. gondii via time-resolved phosphoproteomics and thermal proteome profiling. The waves of phosphoregulation following PKG activation and stimulated Ca2+ release corroborate known physiological changes but identify specific proteins operating in these pathways. Thermal profiling of parasite extracts identified many expected Ca2+-responsive proteins, such as parasite Ca2+-dependent protein kinases. Our approach also identified numerous Ca2+-responsive proteins that are not predicted to bind Ca2+, yet are critical components of the parasite signaling network. We characterized protein phosphatase 1 (PP1) as a Ca2+-responsive enzyme that relocalized to the parasite apex upon Ca2+ store release. Conditional depletion of PP1 revealed that the phosphatase regulates Ca2+ uptake to promote parasite motility. PP1 may thus be partly responsible for Ca2+-regulated serine/threonine phosphatase activity in apicomplexan parasites.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways

Herneisen

Chan

et al. 2022

eLife

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“…Following invasion, protein kinase A catalytic domain 1 (PKAc1) dampens cytosolic Ca 2+ by suppressing cGMP signaling and reducing Ca 2+ uptake ( Jia et al, 2017 ; Uboldi et al, 2018 ). Collectively, the lytic life cycle of tachyzoites is orchestrated spatially and temporally by controlling levels of intracellular Ca 2+ and cyclic nucleotides ( Brown et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma bradyzoites exhibit physiological plasticity of calcium and energy stores controlling motility and egress

Brown

Jones

et al. 2021

eLife

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Toxoplasma gondii has evolved different developmental stages for disseminating during acute infection (i.e. tachyzoites) and for establishing chronic infection (i.e. bradyzoites). Calcium ion (Ca2+) signaling tightly regulates the lytic cycle of tachyzoites by controlling microneme secretion and motility to drive egress and cell invasion. However, the roles of Ca2+ signaling pathways in bradyzoites remain largely unexplored. Here we show that Ca2+ responses are highly restricted in bradyzoites and that they fail to egress in response to agonists. Development of dual-reporter parasites revealed dampened Ca2+ responses and minimal microneme secretion by bradyzoites induced in vitro or harvested from infected mice and tested ex vivo. Ratiometric Ca2+ imaging demonstrated lower Ca2+ basal levels, reduced magnitude, and slower Ca2+ kinetics in bradyzoites compared with tachyzoites stimulated with agonists. Diminished responses in bradyzoites were associated with down-regulation of Ca2+-ATPases involved in intracellular Ca2+ storage in the endoplasmic reticulum (ER) and acidocalcisomes. Once liberated from cysts by trypsin digestion, bradyzoites incubated in glucose plus Ca2+ rapidly restored their intracellular Ca2+ and ATP stores leading to enhanced gliding. Collectively, our findings indicate that intracellular bradyzoites exhibit dampened Ca2+ signaling and lower energy levels that restrict egress, and yet upon release they rapidly respond to changes in the environment to regain motility.

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“…We can emulate these endogenous signaling pathways by treating isolated parasites with zaprinast, which stimulates PKG activation by inhibiting phosphodiesterases that degrade cGMP (Brown et al, 2016;Lourido et al, 2012). Zaprinast-stimulated motility occurs rapidly and in defined sequence in apicomplexans: initially, an increase in cGMP activates parasite protein kinase G (PKG), which phosphorylates substrates and stimulates Ca 2+ release from internal stores (Brown et al, 2020;Lourido and Moreno, 2015). Ca 2+ -dependent protein kinases, such as TgCDPK1 and TgCDPK3, synergize with PKG to effectuate microneme secretion and parasite motility (Brown et al, 2016;Lourido et al, 2012Lourido et al, , 2010McCoy et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

De novo mapping of the apicomplexan Ca²⁺-responsive proteome

Herneisen

Chan

et al. 2022

Preprint

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Apicomplexan parasites cause persistent mortality and morbidity worldwide through diseases including malaria, toxoplasmosis, and cryptosporidiosis. Ca2+ signaling pathways have been repurposed in these eukaryotic pathogens to regulate parasite-specific cellular processes governing the transition between the replicative and lytic phases of the infectious cycle. Despite the presence of conserved Ca2+-responsive proteins, little is known about how specific signaling elements interact to impact pathogenesis. We mapped the Ca2+-responsive proteome of the model apicomplexan T. gondii via time-resolved phosphoproteomics and thermal proteome profiling. The waves of phosphoregulation following PKG activation and stimulated Ca2+ release corroborate known physiological changes but identify specific proteins operating in these pathways. Thermal profiling of parasite extracts identified many expected Ca2+-responsive proteins, such as parasite Ca2+-dependent protein kinases. Our approach also identified numerous Ca2+-responsive proteins that are not predicted to bind Ca2+, yet are critical components of the parasite signaling network. We characterized protein phosphatase 1 (PP1) as a Ca2+-responsive enzyme that relocalized to the parasite apex upon Ca2+ store release. Conditional depletion of PP1 revealed that the phosphatase regulates Ca2+ uptake to promote parasite motility. PP1 may thus be partly responsible for Ca2+-regulated serine/threonine phosphatase activity in apicomplexan parasites.

show abstract

Calcium and cyclic nucleotide signaling networks in Toxoplasma gondii

Cited by 8 publications

References 149 publications

Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways

Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways

Toxoplasma bradyzoites exhibit physiological plasticity of calcium and energy stores controlling motility and egress

De novo mapping of the apicomplexan Ca²⁺-responsive proteome

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Calcium and cyclic nucleotide signaling networks in Toxoplasma gondii

Cited by 8 publications

References 149 publications

Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways

Temporal and thermal profiling of the Toxoplasma proteome implicates parasite Protein Phosphatase 1 in the regulation of Ca2+-responsive pathways

Toxoplasma bradyzoites exhibit physiological plasticity of calcium and energy stores controlling motility and egress

De novo mapping of the apicomplexan Ca2+-responsive proteome

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Product

Resources

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De novo mapping of the apicomplexan Ca²⁺-responsive proteome