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 identify P. falciparum lysophospholipid acyltransferase 1 (PfLPLAT1) and show that PfLPLAT1 is vital for asexual parasite cell cycle progression and cytostome internalization. Deficiency in PfLPLAT1 results in decreased parasitemia and prevents transition to the schizont stage. Parasites lacking PfLPLAT1 also exhibit distinctive omega-shaped vacuoles, indicating disrupted cytostome function. Transcriptomic analyses suggest that this deficiency impacts DNA replication and cell cycle regulation. Mass spectrometry-based enzyme assay and lipidomic analysis demonstrate that recombinant PfLPLAT1 exhibits 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.