A vacuolar iron-transporter homologue acts as a detoxifier in Plasmodium

Ksenija Slavic, Sanjeev Krishna, Aparajita Lahree, Guillaume Bouyer, Kirsten K. Hanson, Iset Vera, Jon K. Pittman, Henry M. Staines & Maria M. Mota

Nat. Commun. 7:10403 (2016) doi: 10.1038.

Speaker: Ming-Yang Wu (吳明陽)                               Time: 14:00~15:00, Mar 16, 2016

Commentator: Dr. Wei-Chen Lin (林威辰 老師)     Place: Room 601

Abstract:

Malaria is a mosquito-borne disease caused by a parasite and WHO estimate of around 600,000 deaths annually, although artemisinin-combination therapies becomes successful. Malaria contains three stages of life cycle: the mosquito stage, the liver stage, the blood stage.  Recently, interference of iron homeostasis is an intriguing way to target malaria parasites as Plasmodium. Iron involves in some essential cellular processes, such as ATP and DNA synthesis [1]. But iron is also toxic when present at high concentrations, which cause reactive oxygen species (ROS) overproduction and cell death [2]. Therefore, all organisms need some strategies to obtain necessary iron and to detoxify any excesses. In yeast and plant cells, excessive iron is sequestered into intracellular organelles by vacuolar iron-transporter (VIT) family proteins and a small amount of cellular iron is present as a metabolically available pool in the cytoplasm, termed the labile iron pool (LIP). In this study, the authors investigate the VIT homologue from the malaria parasites Plasmodium falciparum (PfVIT) and Plasmodium berghei (PbVIT). First, they used CCC1 knockout (ΔCCC1) S. cerevisiae, which can’t transport Fe²⁺ into the vacuole and transform 5′-truncated pfvit (sPfVIT) into S. cerevisiae. Highly expression of sPfVIT significantly can restore the ΔCCC1 phenotype at all Fe²⁺ concentrations. They generate a C-terminal green fluorescent protein (GFP) ormyc fusion of PbVIT in Plasmodium parasites. The fusion protein PbVIT-GFP and PbVIT-myc are expressed in the parasite ER. To demonstrate that Plasmodium VITs act as iron detoxifiers. They created Pbvit gene deficient (Pbvit⁻) parasites by double crossover recombination. Pbvit⁻ parasites significantly reduced in parasite load in both liver and blood stages of infection in mice. Pbvit⁻ parasites also increased LIP levels in blood stages and are more sensitive to increased iron levels in liver stages, leading to either growth defects under excess iron conditions or growth rescue under iron chelating conditions. In conclusion, Plasmodium VITs play a key role in cellular iron detoxification in Plasmodium infection and provide new insights into how iron is regulated within Plasmodium parasites.

Reference:

1. Lytton, S. D., Mester, B., Libman, J., Shanzer, A. & Cabantchik, Z. I. Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis. Blood 84, 910–915 (1994).

2. Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death.Nat. Chem. Biol. 10, 9–17 (2014).