Abstract
Zinc (Zn2+) is the most abundant biological metal ion aside from iron and is an essential element in numerous biological systems, acting as a cofactor for a large number of enzymes and regulatory proteins. Zn2+ must be tightly regulated, as both the deficiency and overabundance of intracellular free Zn2+ are harmful to cells. Zn2+ transporters (ZnTs) play important functions in cells by reducing intracellular Zn2+ levels by transporting the ion out of the cytoplasm. We characterized a Toxoplasma gondii gene (TgGT1_251630, TgZnT), which is annotated as the only ZnT family Zn2+ transporter in T. gondii TgZnT localizes to novel vesicles that fuse with the plant-like vacuole (PLV), an endosome-like organelle. Mutant parasites lacking TgZnT exhibit reduced viability in in vitro assays. This phenotype was exacerbated by increasing zinc concentrations in the extracellular media and was rescued by media with reduced zinc. Heterologous expression of TgZnT in a Zn2+-sensitive Saccharomyces cerevisiae yeast strain partially restored growth in media with higher Zn2+ concentrations. These results suggest that TgZnT transports Zn2+ into the PLV and plays an important role in the Zn2+ tolerance of T. gondii extracellular tachyzoites.IMPORTANCEToxoplasma gondii is an intracellular pathogen of human and animals. T. gondii pathogenesis is associated with its lytic cycle, which involves invasion, replication, egress out of the host cell, and invasion of a new one. T. gondii must be able to tolerate abrupt changes in the composition of the surrounding milieu as it progresses through its lytic cycle. We report the characterization of a Zn2+ transporter of T. gondii (TgZnT) that is important for parasite growth. TgZnT restored Zn2+ tolerance in yeast mutants that were unable to grow in media with high concentrations of Zn2+ We propose that TgZnT plays a role in Zn2+ homeostasis during the T. gondii lytic cycle.
Highlights
Zinc (Zn2ϩ) is the most abundant biological metal ion aside from iron and is an essential element in numerous biological systems, acting as a cofactor for a large number of enzymes and regulatory proteins
With the aim of characterizing the potential role of the plant-like vacuole (PLV) in the survival and thriving of Toxoplasma during its extracellular passage, an essential phase of its lytic cycle, we looked at potential transporters that localize to the PLV and that could function in the transport of ions for which a strict control is required
Zn2ϩ levels need to be tightly controlled; second, there was proteomic evidence for the presence of a zinc transporter in Toxoplasma and in a PLV-enriched fraction (ToxoDB and unpublished data); and third, evidence for the proton gradient needed for its function was demonstrated in previous work [5]
Summary
Zinc (Zn2ϩ) is the most abundant biological metal ion aside from iron and is an essential element in numerous biological systems, acting as a cofactor for a large number of enzymes and regulatory proteins. Heterologous expression of TgZnT in a Zn2ϩ-sensitive Saccharomyces cerevisiae yeast strain partially restored growth in media with higher Zn2ϩ concentrations These results suggest that TgZnT transports Zn2ϩ into the PLV and plays an important role in the Zn2ϩ tolerance of T. gondii extracellular tachyzoites. The resting intracellular free Zn2ϩ concentration is reported to be at picomolar levels [20], and cytosolic zinc-binding proteins exhibit an affinity for Zn2ϩ in the picomolar range [21, 22]. These picomolar concentrations represent less than 0.0001% of total cellular Zn2ϩ, exemplifying the precise control of cytoplasmic free Zn2ϩ in eukaryotic cells. Free Zn2ϩ in the extracellular space was reported to be in the range of 5 to 25 nM in the central nervous system [23], which is more than 1,000-fold higher than the predicted intracellular concentration
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