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The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence

The pathogenesis of Toxoplasma gondii is mainly due to tissue damage caused by the repeating lytic cycles of the parasite. Many proteins localized to the pellicle of the parasite, particularly kinases, have been identified as critical regulators of the Toxoplasma lytic cycle. However, little is know...

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Autores principales: Yang, Chunlin, Blakely, William J., Arrizabalaga, Gustavo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241511/
https://www.ncbi.nlm.nih.gov/pubmed/35603560
http://dx.doi.org/10.1128/msphere.00052-22
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author Yang, Chunlin
Blakely, William J.
Arrizabalaga, Gustavo
author_facet Yang, Chunlin
Blakely, William J.
Arrizabalaga, Gustavo
author_sort Yang, Chunlin
collection PubMed
description The pathogenesis of Toxoplasma gondii is mainly due to tissue damage caused by the repeating lytic cycles of the parasite. Many proteins localized to the pellicle of the parasite, particularly kinases, have been identified as critical regulators of the Toxoplasma lytic cycle. However, little is known about the associated protein phosphatases. Phosphatase of regenerating liver (PRL), a highly conserved tyrosine phosphatase, is an oncoprotein that plays pivotal roles in mammalian cells and typically associates with membranes via a conserved prenylation site. PRL in Toxoplasma has a predicted prenylation motif in the C terminus, like other homologs. We have determined that T. gondii PRL (TgPRL) localizes to the plasma membrane and that disruption of TgPRL results in a defect in the parasite’s ability to attach to host cells. This function is dependent on both TgPRL’s membrane localization and phosphatase activity. Importantly, in vivo experiments have shown that while mice infected with parental strain parasites die within days of infection, those infected with parasites lacking TgPRL not only survive but also develop immunity that confers protection against subsequent infection with wild-type parasites. Immunoprecipitation experiments revealed that the PRL-CNNM (cyclin M) complex, which regulates intracellular Mg(2+) homeostasis in mammalian cells, is also present in Toxoplasma. Consistent with this interaction, parasites lacking TgPRL had higher intracellular Mg(2+) levels than the parental or complemented strains, suggesting TgPRL is involved in regulating intracellular Mg(2+) homeostasis. Thus, TgPRL is a vital regulator of the Toxoplasma lytic cycle and virulence, showing its potential as a target of therapeutic intervention. IMPORTANCE Infection with Toxoplasma gondii can lead to severe and even life-threatening diseases in people with compromised or suppressed immune systems. Unfortunately, drugs to combat the parasite are limited, highly toxic, and ineffective against the chronic stage of the parasite. Consequently, there is a strong demand for the discovery of new treatments. A comprehensive understanding of how the parasite propagates in the host cells and which proteins contribute to the parasite’s virulence will facilitate the discovery of new drug targets. Our study meets this objective and adds new insights to understanding the lytic cycle regulation and virulence of Toxoplasma by determining that the protein phosphatase TgPRL plays a vital role in the parasite’s ability to attach to host cells and that it is essential for parasite virulence.
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spelling pubmed-92415112022-06-30 The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence Yang, Chunlin Blakely, William J. Arrizabalaga, Gustavo mSphere Research Article The pathogenesis of Toxoplasma gondii is mainly due to tissue damage caused by the repeating lytic cycles of the parasite. Many proteins localized to the pellicle of the parasite, particularly kinases, have been identified as critical regulators of the Toxoplasma lytic cycle. However, little is known about the associated protein phosphatases. Phosphatase of regenerating liver (PRL), a highly conserved tyrosine phosphatase, is an oncoprotein that plays pivotal roles in mammalian cells and typically associates with membranes via a conserved prenylation site. PRL in Toxoplasma has a predicted prenylation motif in the C terminus, like other homologs. We have determined that T. gondii PRL (TgPRL) localizes to the plasma membrane and that disruption of TgPRL results in a defect in the parasite’s ability to attach to host cells. This function is dependent on both TgPRL’s membrane localization and phosphatase activity. Importantly, in vivo experiments have shown that while mice infected with parental strain parasites die within days of infection, those infected with parasites lacking TgPRL not only survive but also develop immunity that confers protection against subsequent infection with wild-type parasites. Immunoprecipitation experiments revealed that the PRL-CNNM (cyclin M) complex, which regulates intracellular Mg(2+) homeostasis in mammalian cells, is also present in Toxoplasma. Consistent with this interaction, parasites lacking TgPRL had higher intracellular Mg(2+) levels than the parental or complemented strains, suggesting TgPRL is involved in regulating intracellular Mg(2+) homeostasis. Thus, TgPRL is a vital regulator of the Toxoplasma lytic cycle and virulence, showing its potential as a target of therapeutic intervention. IMPORTANCE Infection with Toxoplasma gondii can lead to severe and even life-threatening diseases in people with compromised or suppressed immune systems. Unfortunately, drugs to combat the parasite are limited, highly toxic, and ineffective against the chronic stage of the parasite. Consequently, there is a strong demand for the discovery of new treatments. A comprehensive understanding of how the parasite propagates in the host cells and which proteins contribute to the parasite’s virulence will facilitate the discovery of new drug targets. Our study meets this objective and adds new insights to understanding the lytic cycle regulation and virulence of Toxoplasma by determining that the protein phosphatase TgPRL plays a vital role in the parasite’s ability to attach to host cells and that it is essential for parasite virulence. American Society for Microbiology 2022-05-23 /pmc/articles/PMC9241511/ /pubmed/35603560 http://dx.doi.org/10.1128/msphere.00052-22 Text en Copyright © 2022 Yang et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Yang, Chunlin
Blakely, William J.
Arrizabalaga, Gustavo
The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence
title The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence
title_full The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence
title_fullStr The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence
title_full_unstemmed The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence
title_short The Tyrosine Phosphatase PRL Regulates Attachment of Toxoplasma gondii to Host Cells and Is Essential for Virulence
title_sort tyrosine phosphatase prl regulates attachment of toxoplasma gondii to host cells and is essential for virulence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241511/
https://www.ncbi.nlm.nih.gov/pubmed/35603560
http://dx.doi.org/10.1128/msphere.00052-22
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