Protein Kinase A Negatively Regulates Ca<sup>2+</sup> signaling in <i>Toxoplasma gondii</i>

Uboldi, Alessandro D.; Wilde, Mary-Louise; McRae, Emi A; Stewart, Rebecca J.; Dagley, Laura F.; Yang, Luning; Katris, Nicholas J.; Hapuarachchi, Sanduni V.; Coffey, Michael; Lehane, Adele M.; Botté, Cyrille Y.; Waller, Ross F.; Webb, Andrew I.; Tonkin, Christopher J.

doi:10.1101/265371

Cited by 4 publications

(2 citation statements)

References 53 publications

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“…It was proposed that PKA down-regulates PKG-dependent signaling leading to egress by potentially activating a phosphodiesterase that would hydrolyze cGMP [52]. In a second study on Toxoplasma PKA the authors proposed that PKA is in the pathway that leads to suppression of cytosolic Ca 2+ right after invasion promoting a decrease in motility and the beginning of intracellular replication [53]. It is clear that Ca 2+ , PKG and PKA signaling pathways crosstalk but we still do not know all the elements involved and the order in which they interact (Fig.…”

Section: The Toxoplasma Calcium Signaling Toolkitmentioning

confidence: 99%

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Triana

Márquez-Nogueras

Vella

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Toxoplasma gondii has a complex life cycle involving different hosts and is dependent on fast responses, as the parasite reacts to changing environmental conditions. T. gondii causes disease by lysing the host cells that it infects and it does this by reiterating its lytic cycle, which consists of host cell invasion, replication inside the host cell, and egress causing host cell lysis. Calcium ion (Ca2+) signaling triggers activation of molecules involved in the stimulation and enhancement of each step of the parasite lytic cycle. Ca2+ signaling is essential for the cellular and developmental changes that support T. gondii parasitism. The characterization of the molecular players and pathways directly activated by Ca2+ signaling in Toxoplasma is sketchy and incomplete. The evolutionary distance between Toxoplasma and other eukaryotic model systems makes the comparison sometimes not informative. The advent of new genomic information and new genetic tools applicable for studying Toxoplasma biology is rapidly changing this scenario. The Toxoplasma genome reveals the presence of many genes potentially involved in Ca2+ signaling, even though the role of most of them is not known. The use of Genetically Encoded Calcium Indicators (GECIs) has allowed studies on the role of novel calcium-related proteins on egress, an essential step for the virulence and dissemination of Toxoplasma. In addition, the discovery of new Ca2+ players is generating novel targets for drugs, vaccines, and diagnostic tools and a better understanding of the biology of these parasites.

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Section: The Toxoplasma Calcium Signaling Toolkitmentioning

confidence: 99%

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Triana

Márquez-Nogueras

Vella

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…PKA is a highly conserved kinase present in all eukaryotes except plants, functioning in diverse signalling processes ranging from metabolic regulation and hormone action to cell differentiation and synaptic long term potentiation underlying memory (Lee et al 2021). In protists and fungi the predominant functions are response to carbon source changes and regulation of developmental transitions, infectivity or sexual dimorphism (Perrin et al 2020;Hitz et al 2021;Uboldi et al 2018;Jia et al 2017;Choi, Jung, and Kronstad 2015;Vaidyanathan et al 2014). Regulation of PKA by cAMP was universally found (Rinaldi et al 2010;Haste et al 2012;Kurokawa et al 2011;Taylor et al 2012), which is why PKA and cAMP-dependent protein kinase are used as synonyms.…”

Section: Introductionmentioning

confidence: 99%

Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens

Ober,

Githure,

Santos

et al. 2023

Preprint

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Cyclic nucleotide binding domains (CNB) confer allosteric regulation by cAMP or cGMP to many signalling proteins, including PKA and PKG. PKA of phylogenetically distantTrypanosomais the first exception as it is cyclic nucleotide independent and responsive to nucleoside analogues (Bachmaier et al. 2019). Here we show that natural nucleosides inosine, guanosine and adenosine are nanomolar affinity CNB ligands and activators of PKA orthologs of the important tropical pathogens T. brucei,T. cruziandLeishmania. The sequence and structural determinants of binding affinity, -specificity and kinase activation of PKAR were established by structure-activity relationship (SAR) analysis, co-crystal structures and mutagenesis. Substitution of 2-3 amino acids in the binding sites is sufficient for conversion of CNB domains from nucleoside to cyclic nucleotide specificity. In addition, a trypanosomatid-specific C-terminal helix (αD) is required for high affinity binding to CNB-B. The αD helix functions as a lid of the binding site that shields ligands from solvent. Selectivity of guanosine for CNB-B and of adenosine for CNB-A results in synergistic kinase activation at low nanomolar concentration. PKA pulldown from rapid lysis establishes guanosine as the predominant ligandin vivoinT. bruceibloodstream forms, whereas guanosine and adenosine seem to synergize in the procyclic developmental stage in the insect vector. We discuss the versatile use of CNB domains in evolution and recruitment of PKA for novel nucleoside-mediated signalling.

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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.

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Protein Kinase A Negatively Regulates Ca²⁺ signaling in Toxoplasma gondii

Abstract: 27The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate 28 between intracellular replicating forms and actively motile extracellular forms that move

Cited by 4 publications

References 53 publications

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens

De novo mapping of the apicomplexan Ca²⁺-responsive proteome

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Protein Kinase A Negatively Regulates Ca2+ signaling in Toxoplasma gondii

Abstract: 27The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate 28 between intracellular replicating forms and actively motile extracellular forms that move

Cited by 4 publications

References 53 publications

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens

De novo mapping of the apicomplexan Ca2+-responsive proteome

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Protein Kinase A Negatively Regulates Ca²⁺ signaling in Toxoplasma gondii

De novo mapping of the apicomplexan Ca²⁺-responsive proteome