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A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress

Fundamental processes that govern the lytic cycle of the intracellular parasite Toxoplasma gondii are regulated by several signalling pathways. However, how these pathways are connected remains largely unknown. Here, we compare the phospho-signalling networks during Toxoplasma egress from its host c...

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Autores principales: Nofal, Stephanie D., Dominicus, Caia, Broncel, Malgorzata, Katris, Nicholas J., Flynn, Helen R., Arrizabalaga, Gustavo, Botté, Cyrille Y., Invergo, Brandon M., Treeck, Moritz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624417/
https://www.ncbi.nlm.nih.gov/pubmed/36265000
http://dx.doi.org/10.1371/journal.ppat.1010901
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author Nofal, Stephanie D.
Dominicus, Caia
Broncel, Malgorzata
Katris, Nicholas J.
Flynn, Helen R.
Arrizabalaga, Gustavo
Botté, Cyrille Y.
Invergo, Brandon M.
Treeck, Moritz
author_facet Nofal, Stephanie D.
Dominicus, Caia
Broncel, Malgorzata
Katris, Nicholas J.
Flynn, Helen R.
Arrizabalaga, Gustavo
Botté, Cyrille Y.
Invergo, Brandon M.
Treeck, Moritz
author_sort Nofal, Stephanie D.
collection PubMed
description Fundamental processes that govern the lytic cycle of the intracellular parasite Toxoplasma gondii are regulated by several signalling pathways. However, how these pathways are connected remains largely unknown. Here, we compare the phospho-signalling networks during Toxoplasma egress from its host cell by artificially raising cGMP or calcium levels. We show that both egress inducers trigger indistinguishable signalling responses and provide evidence for a positive feedback loop linking calcium and cyclic nucleotide signalling. Using WT and conditional knockout parasites of the non-essential calcium-dependent protein kinase 3 (CDPK3), which display a delay in calcium inonophore-mediated egress, we explore changes in phosphorylation and lipid signalling in sub-minute timecourses after inducing Ca(2+) release. These studies indicate that cAMP and lipid metabolism are central to the feedback loop, which is partly dependent on CDPK3 and allows the parasite to respond faster to inducers of egress. Biochemical analysis of 4 phosphodiesterases (PDEs) identified in our phosphoproteomes establishes PDE2 as a cAMP-specific PDE which regulates Ca(2+) induced egress in a CDPK3-independent manner. The other PDEs display dual hydrolytic activity and play no role in Ca(2+) induced egress. In summary, we uncover a positive feedback loop that enhances signalling during egress, thereby linking several signalling pathways.
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spelling pubmed-96244172022-11-02 A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress Nofal, Stephanie D. Dominicus, Caia Broncel, Malgorzata Katris, Nicholas J. Flynn, Helen R. Arrizabalaga, Gustavo Botté, Cyrille Y. Invergo, Brandon M. Treeck, Moritz PLoS Pathog Research Article Fundamental processes that govern the lytic cycle of the intracellular parasite Toxoplasma gondii are regulated by several signalling pathways. However, how these pathways are connected remains largely unknown. Here, we compare the phospho-signalling networks during Toxoplasma egress from its host cell by artificially raising cGMP or calcium levels. We show that both egress inducers trigger indistinguishable signalling responses and provide evidence for a positive feedback loop linking calcium and cyclic nucleotide signalling. Using WT and conditional knockout parasites of the non-essential calcium-dependent protein kinase 3 (CDPK3), which display a delay in calcium inonophore-mediated egress, we explore changes in phosphorylation and lipid signalling in sub-minute timecourses after inducing Ca(2+) release. These studies indicate that cAMP and lipid metabolism are central to the feedback loop, which is partly dependent on CDPK3 and allows the parasite to respond faster to inducers of egress. Biochemical analysis of 4 phosphodiesterases (PDEs) identified in our phosphoproteomes establishes PDE2 as a cAMP-specific PDE which regulates Ca(2+) induced egress in a CDPK3-independent manner. The other PDEs display dual hydrolytic activity and play no role in Ca(2+) induced egress. In summary, we uncover a positive feedback loop that enhances signalling during egress, thereby linking several signalling pathways. Public Library of Science 2022-10-20 /pmc/articles/PMC9624417/ /pubmed/36265000 http://dx.doi.org/10.1371/journal.ppat.1010901 Text en © 2022 Nofal et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nofal, Stephanie D.
Dominicus, Caia
Broncel, Malgorzata
Katris, Nicholas J.
Flynn, Helen R.
Arrizabalaga, Gustavo
Botté, Cyrille Y.
Invergo, Brandon M.
Treeck, Moritz
A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress
title A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress
title_full A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress
title_fullStr A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress
title_full_unstemmed A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress
title_short A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced Toxoplasma gondii egress
title_sort positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in calcium-induced toxoplasma gondii egress
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624417/
https://www.ncbi.nlm.nih.gov/pubmed/36265000
http://dx.doi.org/10.1371/journal.ppat.1010901
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