Characterization of native PfABCG protein in Plasmodium falciparum

Edaye, Sonia; Georges, Elias

doi:10.1016/j.bcp.2015.06.035

Cited by 8 publications

(7 citation statements)

References 51 publications

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“…Based on transcriptomic profiles and data from the literature, six proteins with a potential role in iron transport were identified (Table 1 and 2). Of these, Pf CRT (60) and Pf NRAMP (34) had already been shown to localize to the digestive vacuole (DV) in live parasites (61). The subcellular localization of the other four putative iron transporters ( Pf MRS3, Pf VIT, Pf ZIPCO, and Pf E140) was then examined by endogenous tagging with GFP and confocal imaging of live parasites under physiological control conditions.…”

Section: Resultsmentioning

confidence: 99%

Iron transport pathways in the human malaria parasitePlasmodium falciparumrevealed by RNA-sequencing

Wunderlich,

Kotov,

Votborg-Novél

et al. 2024

Preprint

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Host iron deficiency is protective against severe malaria as the human malaria parasite Plasmodium falciparum depends on free iron from its host to proliferate. Due to the absence of transferrin, ferritin, ferroportin, and a functional heme oxygenase, the parasite's essential pathways of iron acquisition, storage, export, and detoxification differ from those in humans and may thus be excellent targets for therapeutic development. However, the P. falciparum proteins involved in these processes remain largely unknown. Here, we show that parasites cultured in erythrocytes from an iron-deficient donor displayed significantly reduced growth rates compared to those grown in red blood cells from healthy controls. Sequencing of parasite RNA revealed diminished expression of genes involved in overall metabolism, hemoglobin digestion, and metabolite transport under low-iron versus control conditions. Supplementation with hepcidin, a specific ferroportin inhibitor, resulted in increased free iron levels in erythrocytes, enhanced parasite replication, and transcriptional upregulation of genes responsible for merozoite motility and host cell invasion. Based on endogenous GFP tagging of differentially expressed putative transporter genes followed by confocal live-cell imaging, proliferation assays with knockout and knockdown lines, and protein structure predictions, we identified six proteins that are likely required for ferrous iron transport in P. falciparum. PfE140 may be involved in iron uptake into the parasite cytosol across the plasma membrane and PfMRS3 could mediate import of the metal ion into the mitochondrion. PfVIT may transport excess iron from the cytosol into cytoplasmic vesicles, and PfZIPCO could be implicated in Zn2+ and Fe2+ export from these organelles, while PfNRAMP and PfCRT are likely responsible for Fe2+ efflux from the digestive vacuole. Our results provide new insights into the mechanisms of iron transport in P. falciparum and the parasite's response to iron status alterations in the host. PfE140 and PfCRT are particularly promising candidate targets for novel antimalarial drugs, as these are essential to the parasite and lack human orthologs.

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Section: Resultsmentioning

confidence: 99%

Iron transport pathways in the human malaria parasitePlasmodium falciparumrevealed by RNA-sequencing

Wunderlich,

Kotov,

Votborg-Novél

et al. 2024

Preprint

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“…Chemical drugs such as fumagillin and albendazole are effective in controlling microsporidia in bees and grasshoppers ( Guruceaga et al, 2020 ; Johny et al, 2009 ). In Plasmodium falciparum , the PfABCG protein located on the plasma membrane is involved in lipid transport ( Edaye & Georges, 2015 ; Tran et al, 2014 ). Nevertheless, whether the Ycf 1 has the function of substance transport and is the potential drug target need to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Identification and subcellular localization analysis of membrane protein Ycf 1 in the microsporidian Nosema bombycis

Chen

Wei

Chen

et al. 2022

PeerJ

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Microsporidia are obligate intracellular parasites that can infect a wide range of vertebrates and invertebrates including humans and insects, such as silkworm and bees. The microsporidium Nosema bombycis can cause pebrine in Bombyx mori, which is the most destructive disease in the sericulture industry. Although membrane proteins are involved in a wide range of cellular functions and part of many important metabolic pathways, there are rare reports about the membrane proteins of microsporidia up to now. We screened a putative membrane protein Ycf 1 from the midgut transcriptome of the N. bombycis-infected silkworm. Gene cloning and bioinformatics analysis showed that the Ycf 1 gene contains a complete open reading frame (ORF) of 969 bp in length encoding a 322 amino acid polypeptide that has one signal peptide and one transmembrane domain. Indirect immunofluorescence results showed that Ycf 1 protein is distributed on the plasma membrane. Expression pattern analysis showed that the Ycf 1 gene expressed in all developmental stages of N. bombycis. Knockdown of the Ycf 1 gene by RNAi effectively inhibited the proliferation of N. bombycis. These results indicated that Ycf 1 is a membrane protein and plays an important role in the life cycle of N. bombycis.

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“…The differing localisations obtained for the ABC transporter ABCG2 also provide an interesting case. When the subcellular location of the pump was investigated with a polyclonal antibody raised to the N‐terminal half of the protein, it appeared to be present at the surface of the parasite throughout the asexual blood stage as well as at structures immediately beneath the parasite's plasma membrane (Edaye & Georges, ). This pattern of localisation was also observed in gametocytes.…”

Section: The Plasmodium Transportomementioning

confidence: 99%

“…() provide strong support for the presence of ABCG2 at the lipid‐rich structure. Furthermore, it is possible that the plasma membrane localisation reported by Edaye & Georges () for ABCG2 in both asexual and sexual blood‐stage parasites resulted from the capacity of the ABCG antiserum (which was not affinity‐purified) to bind other parasite proteins – for instance, at least one other parasite protein was detected by the ABCG2 antiserum in a western blot assay.…”

Section: The Plasmodium Transportomementioning

confidence: 99%

The transportome of the malaria parasite

Martin

2019

Biological Reviews

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Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two‐thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion‐selective channels that may serve as the pore component of the parasite's ‘new permeation pathways’. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission‐blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.

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Characterization of native PfABCG protein in Plasmodium falciparum

Cited by 8 publications

References 51 publications

Iron transport pathways in the human malaria parasitePlasmodium falciparumrevealed by RNA-sequencing

Iron transport pathways in the human malaria parasitePlasmodium falciparumrevealed by RNA-sequencing

Identification and subcellular localization analysis of membrane protein Ycf 1 in the microsporidian Nosema bombycis

The transportome of the malaria parasite

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