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J Biol Chem. 2019 Apr 16. pii: jbc.RA118.005491. doi: 10.1074/jbc.RA118.005491. [Epub ahead of print]

An apically located hybrid guanylate cyclase-ATPase is critical for the initiation of Ca2+ signalling and motility in Toxoplasma gondii.

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The Walter and Eliza Hall Institute of Medical Research, Australia.
The Walter and Eliza Hall Institute of Medical Research.
The University of Grenoble, France.
Florey Institute of Neuroscience and Mental Health, Australia.
Biochemistry and Molecular Biology, University of Melbourne, Australia.
Monash University, Australia.
Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Australia.


Protozoan parasites of the phylum Apicomplexa actively move through tissue in order to initiate and perpetuate infection. The regulation of parasite motility relies on cyclic nucleotide-dependent kinases, but how these kinases are activated remains unknown. Here, using an array of biochemical and cell biology approaches, we show that the apicomplexan parasite Toxoplasma gondii expresses a large guanylate cyclase protein (TgGC), which contains several upstream ATPase transporter-like domains. We show that TgGC has a dynamic localization, being concentrated at the apical tip in extracellular parasites, which relocates to a more cytosolic distribution during intracellular replication. Conditional TgGC knockdown revealed that this protein is essential for acute-stage tachyzoite growth, as TgGC-deficient parasites were defective in motility, host cell attachment, invasion, and subsequent host cell egress. We show that TgGC is critical for a rapid rise in cytosolic [Ca2+] and for secretion of microneme organelles upon stimulation with a cGMP agonist, but these deficiencies can be bypassed by direct activation of signaling by a Ca2+ ionophore. Further, we found that TgGC is required for transducing changes in extracellular pH and [K+] to activate cytosolic [Ca2+] flux. Together, the results of our work implicate TgGC as a putative signal transducer that activates Ca2+ signaling and motility in Toxoplasma.


Toxoplasma gondii; calcium; cell motility; cyclic GMP (cGMP); cyclic nucleotide

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