Protein Kinase A Negatively Regulates Ca2+ signalling in Toxoplasma gondii

The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate between intracellular replicating forms and actively motile extracellular forms that move through tissue. Parasite cytosolic Ca2+ signalling activates motility, but how this is switched off after invasion is...

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Published inbioRxiv
Main Authors 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 J, Lehane, Adele M, Botte, Cyrille Y, Waller, Ross F, Webb, Andrew I, Tonkin, Christopher J
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.02.2018
Subjects
Acylation
Calcium signalling
Cyclic AMP
Cyclic GMP
Infectivity
Intracellular
Kinases
Motility
Parasites
Perforin
Protein kinase A
Proteins
Secretion
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Summary:The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate between intracellular replicating forms and actively motile extracellular forms that move through tissue. Parasite cytosolic Ca2+ signalling activates motility, but how this is switched off after invasion is not understood. Here we show that the cAMP-dependent Protein Kinase A catalytic subunit 1 (PKAc1) of Toxoplasma is responsible for suppression of Ca2+ signalling upon host cell invasion. We demonstrate that that PKAc1 is sequestered to the parasite periphery by dual acylation of its regulatory subunit PKAr1. Newly invaded PKAc1-deficient parasites exit host cells shortly thereafter in a perforin-like protein 1 (PLP-1)-dependent fashion. We demonstrate that loss of PKAc1 results in an inability to rapidly downregulate cytosolic Ca2+ levels shortly after invasion. Furthermore, we demonstrate that PKAc1 also specifically negatively regulates resting cytosolic Ca2+ in conditions that mimic intracellularity. We also show that cAMP and cGMP have opposing role in microneme secretion, further supporting evidence that cAMP signalling has a suppressive role during motility. Together, this work provides a new paradigm in understanding how Toxoplasma and related apicomplexan parasites regulate infectivity.
DOI:10.1101/265371