PMRT1, a Plasmodium -Specific Parasite Plasma Membrane Transporter, Is Essential for Asexual and Sexual Blood Stage Development

Abstract

Plasmodium falciparum -infected erythrocytes possess multiple compartments with designated membranes. Transporter proteins embedded in these membranes not only facilitate movement of nutrients, metabolites, and other molecules between these compartments, but also are common therapeutic targets and can confer antimalarial drug resistance.

Functional inactivation of Plasmodium falciparum glycogen synthase kinase GSK3 modulates erythrocyte invasion and blocks gametocyte maturation

“…1 A ) parasites with an episomal copy of GDV1 fused to GFP and a destabilization domain under the constitutive cam promoter and induced sexual commitment by the addition of Shield-1 ( Fig. 4 A ) as described recently ( 52 ). After induction of sexual commitment, stage conversion as well as localization of PfGSK3β FL versus PfGSK3β TGD during gametocyte maturation were analyzed in Giemsa-stained blood smears and by fluorescence microscopy.…”

“…As previously described, sexual commitment of P. falciparum can be induced by overexpression of GDV1 (gametocyte development 1) protein providing a robust tool to study gametocyte biology (50,51). We therefore transfected PfGSK3β FL (Figure S1A) and PfGSK3β TGD (Figure 1A) parasites with an episomal copy of GDV1 fused to GFP and a destabilization domain (DD) under the constitutive cam promoter and induced sexual commitment by the addition of Shield-1 (Figure 4A) as described recently (52). After induction of sexual commitment, stage conversion as well as localization of PfGSK3β FL versus PfGSK3β TGD during gametocyte maturation were analyzed in Giemsa-stained blood smears and by fluorescence microscopy.…”

“…Sexual gametocyte stages were produced by inducible overexpression of the sexual commitment factor GDV1 ( gametocyte development 1 ) as previously described ( 50 , 51 ). Integrant cell lines were transfected with an episomal copy of GDV1-GFP fused to a destabilization domain under the constitutive cam promoter ( 52 ) allowing induction of GDV1 expression upon addition of the small molecule Shield-1. Sexual commitment was induced by the addition of 4 μM Shield-1 to a culture containing 1% rings.…”

Updated List of Transport Proteins in Plasmodium falciparum

“…However, precise knowledge of the location of a transport protein and its orientation in the membrane is paramount for understanding its function and the dynamics of solute transport processes between cellular compartments. Therefore, the list presented here contains new information on subcellular localisation and function based on results from recent microscopy experiments (Edaye and Georges, 2015;Haase et al, 2021;Murithi et al, 2021;Wichers et al, 2021;Ahiya et al, 2022;Wichers et al, 2022), solubility assays, immunoprecipitation, proximitydependent biotinylation or subcellular fractionation followed by immunoblot or proteomic analyses (Boucher et al, 2018;Balestra et al, 2021;Bullen et al, 2022), functional and structural studies (Shafik et al, 2020;Beck and Ho, 2021), the presence of targeting signals (Sayers et al, 2018;van Esveld et al, 2021), and Gene Ontology (GO) annotations (Blake et al, 2015). In addition, data on essentiality of P. falciparum genes are usually based on a large piggyBac screen (Zhang et al, 2018) that is known to contain some false-positive and false-negative results (Martin, 2020), highlighting the need for verification by other studies.…”

“…In addition, data on essentiality of P. falciparum genes are usually based on a large piggyBac screen (Zhang et al, 2018) that is known to contain some false-positive and false-negative results (Martin, 2020), highlighting the need for verification by other studies. Thus, results from the latest publications (Jiang et al, 2020;Swift et al, 2020;Oberstaller et al, 2021;Wichers et al, 2022) were included in the list along with information on the presence or absence of human orthologs, as this is important for therapeutic development and was not systematically specified previously. Of note, this mini review focuses mainly on asexual blood-stage parasites and also contains recent data on other stages, as transporters are likely important throughout the life cycle.…”