Abstract
Iron is an essential micronutrient but is also highly toxic. In yeast and plant cells, a key detoxifying mechanism involves iron sequestration into intracellular storage compartments, mediated by members of the vacuolar iron-transporter (VIT) family of proteins. Here we study the VIT homologue from the malaria parasites Plasmodium falciparum (PfVIT) and Plasmodium berghei (PbVIT). PfVIT-mediated iron transport in a yeast heterologous expression system is saturable (Km∼14.7 μM), and selective for Fe2+ over other divalent cations. PbVIT-deficient P. berghei lines (Pbvit−) show a reduction in parasite load in both liver and blood stages of infection in mice. Moreover, Pbvit− parasites have higher levels of labile iron in blood stages and are more sensitive to increased iron levels in liver stages, when compared with wild-type parasites. Our data are consistent with Plasmodium VITs playing a major role in iron detoxification and, thus, normal development of malaria parasites in their mammalian host.
Highlights
Iron is an essential micronutrient but is highly toxic
We show that Plasmodium vacuolar iron-transporter (VIT), expressed throughout the parasite’s life cycle, transport iron and play a major role in iron detoxification in the parasite
Bioinformatic analysis shows that all Plasmodium spp. genomes encode one gene with homology to yeast CCC1 and plant VIT proteins— PF3D7_1223700 in P. falciparum and PBANKA_143860 in P. berghei
Summary
In yeast and plant cells, a key detoxifying mechanism involves iron sequestration into intracellular storage compartments, mediated by members of the vacuolar iron-transporter (VIT) family of proteins. In addition to ferritin found in plastids, plants have several homologues of CCC1, named vacuolar iron transporters (VITs), which are likely to transport iron and other divalent cations such as manganese and zinc into the vacuole for storage and detoxification[11,12,13]. We hypothesized that mechanisms regulating intracellular iron storage in malaria parasites may resemble those of yeast and plants To test this hypothesis, we assessed the ability of Plasmodium falciparum VIT, PfVIT, to transport iron and sought to reveal the role of this protein in the establishment and course of a malaria infection by generating Plasmodium berghei parasites deficient in VIT (Pbvit À ). We show that Plasmodium VITs, expressed throughout the parasite’s life cycle, transport iron and play a major role in iron detoxification in the parasite
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