Protein kinase A negatively regulates Ca.sup.2+ signalling in Toxoplasma gondii
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 Ca.sup.2+ signalling activates motility, but how this is switched off after invasi...
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Published in | PLoS biology Vol. 16; no. 9 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Public Library of Science
12.09.2018
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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 Ca.sup.2+ 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 Ca.sup.2+ 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 prevents rapid down-regulation of cytosolic [Ca.sup.2+ ] levels shortly after invasion. We also provide evidence that loss of PKAc1 sensitises parasites to cyclic GMP (cGMP)-induced Ca.sup.2+ 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. |
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AbstractList | 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 Ca.sup.2+ 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 Ca.sup.2+ 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 prevents rapid down-regulation of cytosolic [Ca.sup.2+ ] levels shortly after invasion. We also provide evidence that loss of PKAc1 sensitises parasites to cyclic GMP (cGMP)-induced Ca.sup.2+ 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. |
Audience | Academic |
Author | Hapuarachchi, Sanduni V Coffey, Michael J Yang, Luning McConville, Malcolm J Dagley, Laura F Waller, Ross F Tonkin, Christopher J Wilde, Mary-Louise Uboldi, Alessandro D Webb, Andrew I McRae, Emi A Katris, Nicholas J Lehane, Adele M Botte, Cyrille Y Stewart, Rebecca J |
Author_xml | – sequence: 1 fullname: Uboldi, Alessandro D – sequence: 2 fullname: Wilde, Mary-Louise – sequence: 3 fullname: McRae, Emi A – sequence: 4 fullname: Stewart, Rebecca J – sequence: 5 fullname: Dagley, Laura F – sequence: 6 fullname: Yang, Luning – sequence: 7 fullname: Katris, Nicholas J – sequence: 8 fullname: Hapuarachchi, Sanduni V – sequence: 9 fullname: Coffey, Michael J – sequence: 10 fullname: Lehane, Adele M – sequence: 11 fullname: Botte, Cyrille Y – sequence: 12 fullname: Waller, Ross F – sequence: 13 fullname: Webb, Andrew I – sequence: 14 fullname: McConville, Malcolm J – sequence: 15 fullname: Tonkin, Christopher J |
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SubjectTerms | Calcium ions Cellular signal transduction Microbiological research Physiological aspects Protein kinases Toxoplasma |
Title | Protein kinase A negatively regulates Ca.sup.2+ signalling in Toxoplasma gondii |
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