PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking.
Polyphosphorylated phosphoinositides (PIPs) are potent second messengers, which trigger a wide variety of signaling and trafficking events in most eukaryotic cells. However, the role and metabolism of PIPs in malaria parasite Plasmodium have remained largely unexplored. Our present studies suggest that PfPI3K, a novel phosphatidylinositol-3-kinase (PI3K) in Plasmodium falciparum, is exported to the host erythrocyte by the parasite in an active form. PfPI3K is a versatile enzyme as it can generate various 3'-phosphorylated PIPs. In the parasite, PfPI3K was localized in vesicular compartments near the membrane and in its food vacuole. PI3K inhibitors wortmannin and LY294002 were effective against PfPI3K and were used to study PfPI3K function. We found that PfPI3K is involved in endocytosis from the host and trafficking of hemoglobin in the parasite. The inhibition of PfPI3K resulted in entrapment of hemoglobin in vesicles in the parasite cytoplasm, which prevented its transport to the food vacuole, the site of hemoglobin catabolism. As a result, hemoglobin digestion, which is a source of amino acids necessary for parasite growth, was attenuated and caused the inhibition of parasite growth.
Vaid
Ankush
A
Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi 110067, India.
Ranjan
Ravikant
R
Smythe
Wynand A
WA
Hoppe
Heinrich C
HC
Sharma
Pushkar
P
D000730:Androstadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology*; D006454:Hemoglobins / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000502:physiology; D006801:Humans; D016778:Malaria, Falciparum / Q000378:metabolism / Q000469:parasitology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D014617:Vacuoles / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D006454:Hemoglobins; D009025:Morpholines; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin