Abstract
Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are particularly important for medically relevant pathogens, such as malaria parasites. Here we present a comprehensive genetic analysis of 35 orphan transport proteins of Plasmodium berghei during its life cycle in mice and Anopheles mosquitoes. Six genes, including four candidate aminophospholipid transporters, are refractory to gene deletion, indicative of essential functions. We generate and phenotypically characterize 29 mutant strains with deletions of individual transporter genes. Whereas seven genes appear to be dispensable under the experimental conditions tested, deletion of any of the 22 other genes leads to specific defects in life cycle progression in vivo and/or host transition. Our study provides growing support for a potential link between heavy metal homeostasis and host switching and reveals potential targets for rational design of new intervention strategies against malaria.
Highlights
Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are important for medically relevant pathogens, such as malaria parasites
Membrane transport proteins (MTP) transfer compounds across biological membranes and encompass diverse gene families, namely ion channels, ATP-dependent pumps and secondary active porters including those of the major facilitator superfamily
Few systematic experimental genetics studies of MTPs have been reported for any organism and merely in the context of genome-wide collections of gene deletion mutants in model organisms, such as Saccharomyces cerevisiae[13,14]
Summary
Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are important for medically relevant pathogens, such as malaria parasites. Membrane transport proteins (MTP) transfer compounds across biological membranes and encompass diverse gene families, namely ion channels, ATP-dependent pumps and secondary active porters including those of the major facilitator superfamily Together they play important physiological roles in, for example, nutrient uptake, disposal of waste products, shuttling of metabolites between organelles, and generation and maintenance of the electrochemical gradient. In the search for targets for novel prophylactic, therapeutic and transmission-blocking intervention strategies to fight malaria, we report here a broad characterization of the importance of orphan MTP orthologues during the complete life cycle of the murine malaria model parasite Plasmodium berghei by relatively fast and efficient experimental genetics approaches
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