PfVPS45 Is Required for Host Cell Cytosol Uptake by Malaria Blood Stage Parasites

During development in human erythrocytes, the malaria parasite Plasmodium falciparum internalizes a large part of the cellular content of the host cell. The internalized cytosol, consisting largely of hemoglobin, is transported to the parasite’s food vacuole where it is degraded, providing nutrients and space for growth. This host cell cytosol uptake (HCCU) is crucial for parasite survival but the parasite proteins mediating this process remain obscure. Here, we identify P. falciparum VPS45 as an essential factor in HCCU. Conditional inactivation of PfVPS45 led to an accumulation of host cell cytosol-filled vesicles within the parasite and inhibited the delivery of hemoglobin to the parasite's digestive vacuole, resulting in arrested parasite growth. A proportion of these HCCU vesicle intermediates was positive for phosphatidylinositol 3-phosphate, suggesting endosomal characteristics. Thus PfVPS45 provides insight into the elusive machinery of the ingestion pathway in a parasite that contains an endolysosomal system heavily repurposed for protein secretion. [Display omitted] •Inactivation of VPS45 abolishes the growth of malaria blood stage parasites•VPS45 is located near the parasite's food vacuole and Golgi•VPS45 is needed for the transport of host cell cytosol to the parasite's food vacuole•Host cell cytosol-filled transport vesicles display the endosomal marker PI(3)P To obtain nutrients and space essential for growth, malaria blood stage parasites engulf the host cell cytosol through unclear mechanisms. Jonscher et al. show that parasite VPS45 is essential for this process and that conditional inactivation of VPS45 prevents the delivery of host cell material to the parasite's digestive vacuole.