Biology subjects

Tokumasu, F.

Publications and source records attributed to Tokumasu, F..

3 recordsLinked to original sources

bioRxiv2025

Plasmodium falciparum diacylglycerol acyltransferase maintains phospholipid homeostasis to regulate sexual differentiation, ER stress, and cytoadhesion

Plasmodium falciparum is the causative agent of human malaria, a life-threating infectious disease that imposes a major global health burden. Lipid metabolism is indispensable for this parasites replication and survival, yet most of the molecular components and mechanisms involved remain poorly understood. In eukaryotes, lipid droplets (LDs) serve as dynamic organelles that store neutral lipids (NLs), buffer lipotoxic stress, and regulate signaling pathways, with their biogenesis controlled by diacylglycerol o-acyltransferases (DGATs). Although P. falciparum encodes a putative DGAT (PF3D7_0322300), its role in the parasite life cycle has not been elucidated. We generated conditional PfDGAT-knockout parasites to investigate the enzymes functional significance. PfDGAT deficiency led to parasite death, accompanied by reduced LD formation, elevated phospholipid levels, and induction of ER stress. Moreover, PfDGAT deletion altered protein trafficking, resulting in the decreased cytoadherence of parasite-infected erythrocytes to human brain microvascular endothelial cells, and suppressed parasite sexual differentiation. Thus, PfDGAT deletion affected multiple aspects of the parasites life cycle, highlighting its critical role in parasite survival and pathogenesis. Our findings provide new insights into parasite lipid homeostasis and highlight DGAT as a potential target of antimalarial intervention.

microbiology↗

bioRxiv2024

Glycolytic enzymes form membrane-less condensates in the malaria parasite Plasmodium falciparum by sensing glucose levels

Recent studies have shown that liquid-liquid phase separation (LLPS) in cells can regulate essential cellular events, including metabolic processes. Glycolytic bodies (G-bodies) are biomolecular condensates formed through the LLPS of glycolytic enzymes, and they accelerate glycolysis to overcome hypoxic stress in several organisms. Although the asexual blood stage (ABS) of the human malaria parasite Plasmodium falciparum highly depends on glycolysis for energy production, there have been no reports of the formation of such G-bodies throughout the parasites lifecycle. Using fluorescence tagging and live imaging, we found that G-body-like condensates containing phosphofructokinase 9 (PFK9) and phosphoglycerate kinase (PGK) were formed in the parasite cells after long-term culture under conditions of low glucose. These G-body-like structures appeared stable, but membrane staining and osmotic stress experiments suggested that the observed condensates were not associated with lipid membrane. Further microscopic observations and mathematical analyses of high signal-to-noise ratio images indicated that small condensates were formed transiently first, and these then gradually grew and stabilized in the cytosol. These results suggested that the formation of glycolytic enzyme condensates may be an important cellular response for adapting to blood sugar level oscillations in the host and maintaining the parasites multiplication in the ABS. Significance statementGlycolytic bodies (G-bodies), which are biomolecular condensates formed through the liquid-liquid phase separation of glycolytic enzymes, can accelerate glycolysis to produce energy and overcome hypoxic stress. The parasites that cause malaria depend on glycolysis for energy production, but there have been no reports that these parasites form G-bodies. We demonstrated that membrane-less G-body-like structures formed in media containing low levels of glucose. Small condensates appeared first and over time, the condensates became larger and more stable. The formation of glycolytic enzyme condensates may be important for the malaria parasite to adapt to fluctuating blood sugar levels in the host. These results further our understanding of the cellular mechanisms for the survival of malaria parasites.

cell biology↗

bioRxiv2024

Pivotal roles of Plasmodium falciparum lysophospholipid acyltransferase 1 in cell cycle progression and cytostome internalization

The rapid intraerythrocytic replication of Plasmodium falciparum, a deadly species of malaria parasite, requires a quick but constant supply of phospholipids to support marked cell membrane expansion. In the malarial parasite, many enzymes functioning in phospholipid synthesis pathway have not been identified or characterized. Here, we identified P. falciparum lysophospholipid acyltransferase 1 (PfLPLAT1) and showed that PfLPLAT1 is vital for asexual parasite cell cycle progression and cytostome internalization. Deficiency in PfLPLAT1 resulted in decreased parasitemia and prevented transition to the schizont stage. Parasites lacking PfLPLAT1 also exhibited distinctive omega-shaped vacuoles, indicating disrupted cytostome function. Transcriptomic analyses suggested that this deficiency impacted DNA replication and cell cycle regulation. Mass spectrometry-based enzyme assay and lipidomic analysis demonstrated that recombinant PfLPLAT1 exhibited lysophospholipid acyltransferase activity with a preference for unsaturated fatty acids as its acyl donors and lysophosphatidic acids as an acceptor, with its conditional knockout leading to abnormal lipid composition and marked morphological and developmental changes including stage arrest. These findings highlight PfLPLAT1 as a potential target for antimalarial therapy, particularly due to its unique role and divergence from human orthologs.

microbiology↗