PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking

Vaid, Ankush; Ranjan, Ravikant; Smythe, Wynand; Hoppe, Heinrich C.; Sharma, Pushkar

doi:10.1182/blood-2009-08-238972

Cited by 134 publications

(155 citation statements)

References 36 publications

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“…These lipids are generally not found in unicellular organisms, where only class III PI3-kinases are present. A recent publication reports that P. falciparum PfPI3-kinase immunoprecipitated from infected red blood cell extracts was capable of phosphorylating PI, PI4P, and PI(4,5)P 2 in vitro (54) and could explain the presence of PI(3,4)P 2 and PI(3,4,5)P 3 that we observed in P. falciparum-infected erythrocytes. Our results clearly showed that in intact P. falciparum-infected erythrocytes, PI3P is by far the most abundant phosphoinositide phosphorylated at position 3 (87.5% Ϯ 6.1% [mean Ϯ SEM; n ϭ 8]).…”

Section: Discussionsupporting

confidence: 61%

“…The food vacuole is a compartment with "lysosome-like" functions in Plasmodium, and association of PI3P with its membrane is in accordance with the PI3P-mediated function in transport to- ward the lysosome in other organisms. Indeed, it has very recently been shown that treatment of parasite cultures with the PI3-kinase inhibitors wortmannin and LY294002 inhibited endocytosis within the parasite, resulted in entrapment of hemoglobin vesicles in the parasite cytoplasm, and prevented their fusion with the food vacuole, suggesting that PI3-kinase is involved in endocytosis from the host and the trafficking of hemoglobin in the parasite (54). The authors also reported that PfPI3-kinase was in part exported to the red blood cell cytosol.…”

Section: Discussionmentioning

confidence: 99%

“…We therefore could not test this unexpected observation, and we did not attempt to separate parasite membranes from host cell membranes after metabolic labeling of phosphoinositides because of the prohibiting levels of radioactivity necessary for their identification. Finally, PfPI3-kinase has also been immunolocalized within the food vacuole (54). In addition, the only FYVE domain-containing protein of P. falciparum, which has been shown to bind PI3P in vitro, has also been localized to the lumen of the food vacuole; however, this localization was independent of the FYVE domain, and thus independent of PI3P-binding (35).…”

Section: Discussionmentioning

confidence: 99%

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Phosphatidylinositol 3-Phosphate, an Essential Lipid in Plasmodium, Localizes to the Food Vacuole Membrane and the Apicoplast

et al. 2010

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Phosphoinositides are important regulators of diverse cellular functions, and phosphatidylinositol 3-monophosphate (PI3P) is a key element in vesicular trafficking processes. During its intraerythrocytic development, the malaria parasite Plasmodium falciparum establishes a sophisticated but poorly characterized protein and lipid trafficking system. Here we established the detailed phosphoinositide profile of P. falciparum-infected erythrocytes and found abundant amounts of PI3P, while phosphatidylinositol 3,5-bisphosphate was not detected. PI3P production was parasite dependent, sensitive to a phosphatidylinositol-3-kinase (PI3-kinase) inhibitor, and predominant in late parasite stages. The Plasmodium genome encodes a class III PI3-kinase of unusual size, containing large insertions and several repetitive sequence motifs. The gene could not be deleted in Plasmodium berghei, and in vitro growth of P. falciparum was sensitive to a PI3-kinase inhibitor, indicating that PI3-kinase is essential in Plasmodium blood stages. For intraparasitic PI3P localization, transgenic P. falciparum that expressed a PI3P-specific fluorescent probe was generated. Fluorescence was associated mainly with the membrane of the food vacuole and with the apicoplast, a four-membrane bounded plastid-like organelle derived from an ancestral secondary endosymbiosis event. Electron microscopy analysis confirmed these findings and revealed, in addition, the presence of PI3P-positive single-membrane vesicles. We hypothesize that these vesicles might be involved in transport processes, likely of proteins and lipids, toward the essential and peculiar parasite compartment, which is the apicoplast. The fact that PI3P metabolism and function in Plasmodium appear to be substantially different from those in its human host could offer new possibilities for antimalarial chemotherapy.Phosphatidylinositol is a crucial phospholipid in eukaryotic cells. It is a structural membrane lipid, and phosphorylation of the hydroxyl groups of its inositol head group by specific lipid kinases leads to the production of seven different phosphoinositide species, which have been found to be enriched in distinct cellular compartments. They play key roles in a multitude of cellular processes, such as membrane traffic, cell motility, cytoskeletal reorganization, DNA synthesis, the cell cycle, adhesion, and signal transduction (9). Approximately 1% of total lipids in mammalian cells are phosphoinositides, mainly phosphatidylinositol 4-monophosphate (PI4P) and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] (45). Derivatives phosphorylated at the 3 position are considerably less abundant in mammalian cells. Phosphatidylinositol 3-monophosphate (PI3P) is a ubiquitous lipid in eukaryotic cells and is present in small amounts in mammalian cells (classically Ͻ15% of PI4P), while PI3P is as abundant as PI4P in the yeast Saccharomyces cerevisiae (2). It has been suggested that one of the functions of these lipids is to establish membrane identity (46); PI4P predominates at the Gol...

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phosphatidylinositol 3-Phosphate, an Essential Lipid in Plasmodium, Localizes to the Food Vacuole Membrane and the Apicoplast

et al. 2010

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“…52 Ablation of Vps34 prevents the formation of autophagosomes. 53 The Plasmodium genome encoded one predicted Vps34-type enzyme containing the characteristic domains of class III PtdIns 3-kinases (e.g., a calcium/lipid-binding C2 domain, a PtdIns 3-kinase family accessory domain and a C-terminal PtdIns 3-and PtdIns 4-kinase catalytic domain). Surprisingly, PtdIns3K (the P. falciparum PIK3C3 ortholog) has been shown to localize at the food vacuole and host plasma membrane during the blood stage.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, PtdIns3K (the P. falciparum PIK3C3 ortholog) has been shown to localize at the food vacuole and host plasma membrane during the blood stage. 53 It will be interesting to examine whether Plasmodium PtdIns3K participates in the formation of autophagosomes budding off from the membrane of the apicoplast as described for mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the ATG8-conjugation system in 2Plasmodiumspecies with special focus on the liver stage

et al. 2013

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Keywords: malaria, Plasmodium liver forms, cellular differentiation, autophagy-related genes, ATG8, apicoplast Abbreviations: ACP, acyl carrier protein; ATG, autophagy-related (gene); ATG, autophagy-related (protein); GABARAP, GABA(A) receptor-associated protein; GFP, green fluorescent protein; IEM, immunoelectron microscopy; IFA, immunofluorescence assays; LC3, microtubule-associated protein 1 light chain 3; mCherry, mCherry red fluorescent protein; ORF, open reading frame; PbATG3, Plasmodium berghei ATG3; PbATG7, Plasmodium berghei ATG7; PbATG8, Plasmodium berghei ATG8; PGK, phosphoglycerate kinase; PDM, product of the differences from the mean; PE, phosphatidylethanolamine; PfATG8, Plasmodium falciparum ATG8; p.i., post-infection; prApe1, precursor form of aminopeptidase I; PtdIns3P, phosphatidylinositol 3-phosphate; PV, parasitophorous vacuolePlasmodium parasites successfully colonize different habitats within mammals and mosquitoes, and adaptation to various environments is accompanied by changes in their organelle composition and size. Previously, we observed that during hepatocyte infection, Plasmodium discards organelles involved in invasion and expands those implicated in biosynthetic pathways. We hypothesized that this process is regulated by autophagy. Plasmodium spp. possess a rudimentary set of known autophagy-related proteins that includes the ortholog of yeast atg8. in this study, we analyzed the activity of the aTG8-conjugation pathway over the course of the lifecycle of Plasmodium falciparum and during the liver stage of Plasmodium berghei. We engineered a transgenic P. falciparum strain expressing mcherry-PfaTG8. These transgenic parasites expressed mcherry-PfaTG8 in human hepatocytes and erythrocytes, and in the midgut and salivary glands of Anopheles mosquitoes. in all observed stages, mcherry-PfaTG8 was localized to tubular structures. Our eM and colocalization studies done in P. berghei showed the association of PbaTG8 on the limiting membranes of the endosymbiont-derived plastid-like organelle known as the apicoplast. interestingly, during parasite replication in hepatocytes, the association of PbaTG8 with the apicoplast increases as this organelle expands in size. PbATG3, PbATG7 and PbATG8 are cotranscribed in all parasitic stages. Molecular analysis of PbaTG8 and PbaTG3 revealed a novel mechanism of interaction compared with that observed for other orthologs. This is further supported by the inability of Plasmodium aTG8 to functionally complement atg8Δ yeast or localize to autophagosomes in starved mammalian cells. altogether, these data suggests a unique role for the aTG8-conjugation system in Plasmodium parasites.

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Signaling in malaria parasites

Sharma

Kumar

2016

Advances in Malaria Research

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PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking

Cited by 134 publications

References 36 publications

Phosphatidylinositol 3-Phosphate, an Essential Lipid in Plasmodium, Localizes to the Food Vacuole Membrane and the Apicoplast

Phosphatidylinositol 3-Phosphate, an Essential Lipid in Plasmodium, Localizes to the Food Vacuole Membrane and the Apicoplast

Characterization of the ATG8-conjugation system in 2Plasmodiumspecies with special focus on the liver stage

Signaling in malaria parasites

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