Phosphatase UBLCP1 is required for the growth, virulence and mitochondrial integrity of Toxoplasma gondii

TL;DR

A phosphatase called UBLCP1 is crucial for the growth and virulence of the parasite Toxoplasma gondii, and its absence disrupts mitochondrial function and reduces the parasite's ability to cause disease.

Contribution

This study identifies UBLCP1 as a key phosphatase required for mitochondrial integrity and virulence in Toxoplasma gondii, suggesting it as a potential drug or vaccine target.

Findings

UBLCP1-deficient T. gondii tachyzoites show collapsed mitochondria and reduced growth and proliferation.

UBLCP1 is essential for the virulence of T. gondii in mice, as UBLCP1-deficient parasites fail to cause lethal infections.

Phosphoproteomic analysis reveals UBLCP1 influences protein turnover and trafficking in T. gondii.

Abstract

The mitochondrion is proposed as an ideal target organelle for the control of apicomplexan parasites, whose integrity depends on well-controlled protein import, folding, and turnover. The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) was found to be associated with the mitochondrial integrity in Toxoplasma gondii. However, little is known about the roles and mechanisms of UBLCP1 in this apicomplexan parasite.

The subcellular localization of UBLCP1 in the tachyzoites of T. gondii was determined by an indirect immunofluorescence assay. The roles of UBLCP1 in the growth, cell cycle, and division of T. gondii were assessed by knocking out this molecule in the tachyzoites. Comparative phosphoproteomics between the UBLCP1-deficient and wild-type tachyzoites were performed to understand the roles of UBLCP1 in T. gondii. The virulence of UBLCP1-deficient tachyzoites of T. gondii was tested in mice.

UBLCP1 is expressed in the nucleus and cytoplasm of T. gondii tachyzoites. Tachyzoites lacking UBLCP1 exhibit collapsed mitochondrion, decreased mitochondrial membrane potential, and compromised growth and proliferation in vitro. Proteins involved in protein turnover and intracellular trafficking have been found differentially phosphorylated in the UBLCP1-deficient tachyzoites compared with the control. Deletion of UBLCP1 also shows that this phosphatase is essential for the propagation and virulence of T. gondii tachyzoites. Mice immunized with UBLCP1-deficient T. gondii tachyzoites survived challenges with the virulent PRU or VEG strain.

UBLCP1 is required for the mitochondrial integrity and essential in the lytic cycle (e.g., host cell invasion and parasite replication) in vitro and the pathogenicity of this parasite in vivo. UBLCP1 is a candidate target for a vaccine or a drug for toxoplasmosis in animals.

The online version contains supplementary material available at 10.1186/s13071-025-06766-3.

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