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

Autor: Nofal SD; Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, London, United Kingdom., Dominicus C; Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, London, United Kingdom., Broncel M; Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, London, United Kingdom.; Protein Analysis and Proteomics Platform, The Francis Crick Institute, London, United Kingdom., Katris NJ; Apicolipid Team, Institute for Advance Biosciences, CNRS UMR5309, Université Grenoble Alpes, INSERM U1209, Grenoble, France., Flynn HR; Protein Analysis and Proteomics Platform, The Francis Crick Institute, London, United Kingdom., Arrizabalaga G; University of Indianapolis, School of Medicine, Indianapolis, Indiana, United States of America., Botté CY; Apicolipid Team, Institute for Advance Biosciences, CNRS UMR5309, Université Grenoble Alpes, INSERM U1209, Grenoble, France., Invergo BM; Translational Research Exchange at Exeter, University of Exeter, Exeter, United Kingdom., Treeck M; Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, London, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2022 Oct 20; Vol. 18 (10), pp. e1010901. Date of Electronic Publication: 2022 Oct 20 (Print Publication: 2022).
DOI: 10.1371/journal.ppat.1010901
Abstrakt: 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 Ca2+ 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 Ca2+ induced egress in a CDPK3-independent manner. The other PDEs display dual hydrolytic activity and play no role in Ca2+ induced egress. In summary, we uncover a positive feedback loop that enhances signalling during egress, thereby linking several signalling pathways.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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