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 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 Mg²¹ homeostasis in mammalian cells, is also present in Toxoplasma. Consistent with this interaction, parasites lacking TgPRL had higher intracellular Mg²¹ levels than the parental or complemented strains, suggesting TgPRL is involved in regulating intracellular Mg²¹ homeostasis. Thus, TgPRL is a vital regulator of the Toxoplasma lytic cycle and virulence, showing its potential as a target of therapeutic intervention.