Protein kinase A negatively regulates Ca2+ signalling in Toxoplasma gondii

Uboldi, AD; Wilde, ML; McRae, EA; Stewart, RJ; Dagley, LF; Yang, L; Katris, NJ; Hapuarachchi, SV; Coffey, MJ; Lehane, AM; Botte, CY; Waller, RF; Webb, AI; McConville, MJ; Tonkin, CJ

Author(s): Uboldi, AD; Wilde, ML; McRae, EA; Stewart, RJ; Dagley, LF; Yang, L; Katris, NJ; Hapuarachchi, SV; Coffey, MJ; Lehane, AM; Botte, CY; Waller, RF; Webb, AI; McConville, MJ; Tonkin, CJ;
Details: Publication Year 2018-09-12,Volume 16,Issue #9,Page e2005642
Journal Title: PLoS Biology
Publication Type: Journal Article
Abstract: The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate between intracellular replicating stages and actively motile extracellular forms that move through tissue. Parasite cytosolic Ca2+ signalling activates motility, but how this is switched off after invasion is complete to allow for replication to begin is not understood. Here, we show that the cyclic adenosine monophosphate (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 PKAc1 is sequestered to the parasite periphery by dual acylation of PKA regulatory subunit 1 (PKAr1). Upon genetic depletion of PKAc1 we show that newly invaded parasites exit host cells shortly thereafter, in a perforin-like protein 1 (PLP-1)-dependent fashion. Furthermore, we demonstrate that loss of PKAc1 negatively regulates resting cytosolic [Ca2+] in extracellular tachyzoites and is also required to rapidly down-regulate cytosolic Ca2+ levels shortly after invasion. We also provide evidence that loss of PKAc1 sensitises parasites to cyclic GMP (cGMP)-induced Ca2+ signalling, thus demonstrating a functional link between cAMP and these other signalling modalities. Together, this work provides a new paradigm in understanding how Toxoplasma and related apicomplexan parasites regulate infectivity.
Publisher: PLOS
Research Division(s): Infection And Immunity; Systems Biology And Personalised Medicine
PubMed ID: 30208022
Publisher's Version: https://doi.org/10.1371/journal.pbio.2005642
NHMRC Grants: NHMRC/1123218, NHMRC/1047806, NHMRC/1025598,
ARC Grants: ARC/FT120100164, ARC/DE160101035,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-09-14 02:33:45

Last Modified: 2018-09-14 02:47:02