Developmental-stage-specific triacylglycerol biosynthesis, degradation and trafficking as lipid bodies inPlasmodium falciparum-infected erythrocytes

Abstract

Triacylglycerol (TAG) serves as a major energy storage molecule in eukaryotes. In Plasmodium, however, this established function of TAG appears unlikely, despite detecting previously considerable amount of TAG associated with intraerythrocytic parasites, because plasmodial cells have very little capacity to oxidize fatty acids. Thus, it is plausible that TAG and its biosynthesis in Plasmodium have other functions. As a first step in understanding the biological significance of TAG and its biosynthesis to the intraerythrocytic proliferation of Plasmodium falciparum, we performed detailed characterization of TAG metabolism and trafficking in parasitized erythrocyte. Metabolic labeling using radiolabeled-oleic and palmitic acids in association with serum albumin, which have been shown to be among the serum essential factors for intraerythrocytic proliferation of P. falciparum, revealed that accumulation of TAG was strikingly pronounced from trophozoite to schizont, whereas TAG degradation became active from schizont to segmented schizont; the consequent products, free fatty acids, were released into the medium during schizont rupture and/or merozoite release. These results were further supported by visualization of lipid bodies through immunofluorescence and electron microscopy. At the schizont stages, there is some evidence that the lipid bodies are partly localized in the parasitophorous vacuole. Interestingly, the discrete formation and/or trafficking of lipid bodies are inhibited by brefeldin A and trifluoperazine. Inhibition by trifluoperazine hints at least that a de novo TAG biosynthetic pathway via phosphatidic acid contributes to lipid body formation. Indeed, biochemical analysis reveals a higher activity of acyl-CoA:diacylglycerol acyltransferase, the principal enzyme in the sn-glycerol-3-phosphate pathway for TAG synthesis, at trophozoite and schizont stages. Together, these results establish that TAG metabolism and trafficking in P. falciparum-infected erythrocyte occurs in a stage-specific manner during the intraerythrocytic cycle and we propose that these unique and dynamic cellular events participate during schizont rupture and/or merozoite release.

Fatty Acids fromPlasmodium falciparumDown-Regulate the Toxic Activity of Malaria Glycosylphosphatidylinositols

“…Intraerythrocytic parasites have the capacity to synthesize triacylglycerol from the mature trophozoite stage to the schizont stage. Triacylglycerol is degraded into free fatty acids at the later stages (28). The resulting products, free fatty acids, are released into the medium during schizont rupture and/or merozoite release (28).…”

“…Triacylglycerol is degraded into free fatty acids at the later stages (28). The resulting products, free fatty acids, are released into the medium during schizont rupture and/or merozoite release (28). This explains how the malarial fatty acids can act on host cells.…”

Emerging Role of Lipid Droplets in Host/Pathogen Interactions

“…Terminally differentiated erythrocytes lack internal organelles, the machinery for de novo protein and lipid synthesis, and trafficking machineries. The main component of mature erythrocytes is hemoglobin, which is degraded and used as an amino acid source by P. falciparum.Infected erythrocytes display a dramatic increase in phospholipid and triglyceride content, but not in cholesterol esters (94,95). Interestingly, to produce triglyceride-rich LDs, the parasite encodes its own DGAT enzyme (a homolog to membrane-bound O-acyltransferases), which is expressed specifically in the intra-erythrocyte stage and is essential for the proliferation of the parasite (95-97).…”

Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA

“…Whereas the transfer rates of acyl chains other than C14 are extremely slow compared with myristate ( 33,44,47 ), NMT proteins bind the very abundant C 16 -CoA molecule with the same affi nity as C 14 -CoA, a minor acyl-CoA in cells ( 26,28,29,33,49 ). may offer another strategy to affect the activity of the parasite NMT and its association to ACBD6 (59)(60)(61).…”