The apicomplexan DedA superfamily protein VMP1 is crucial for the biogenesis and function of secretory organelles

Abstract

Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, contain specialized secretory organelles like micronemes, rhoptries, and dense granules, whose secretions are essential for various parasite activities. As lipid mobilization is key for organelle biogenesis and function, we investigated if the DedA superfamily lipid scramblase vacuole membrane protein 1 (VMP1) has a role in the biogenesis and function of apicomplexan secretory organelles. Our study demonstrates that VMP1 of P. falciparum (PfVMP1) and T. gondii (TgVMP1) localize to ER. Depletion of TgVMP1 caused reduced microneme secretion, loss of rhoptries and their decreased secretion, and accumulation of dense granules in ER, indicating a key role of TgVMP1 in the biogenesis and function of these organelles. Consistently, TgVMP1 depletion adversely affected parasite development, motility, host cell invasion, and egress. TgVMP depletion decreased the number of lipid droplets, which is similar to the phenotype of ER lipid scramblase-deficient cells and suggests that TgVMP1 is a lipid scramblase. Importantly, both human VMP1 and PfVMP1 localized to ER of TgVMP1-depleted parasites and rescued the depleted parasites, indicating a crucial role of an ER-resident lipid scramblase in the biogenesis and function of secretory organelles. The essentiality of TgVMP1 for parasite development and likely functional conservation of apicomplexan VMP1 proteins highlight their drug-target potential for developing pan-apicomplexan drugs.