Abstract
The Apicomplexan parasite responsible for the most virulent form of malaria, Plasmodium falciparum, invades human erythrocytes through multiple ligand–receptor interactions. The P. falciparum reticulocyte-binding protein homologue (PfRh or PfRBL) family have been implicated in the invasion process but their exact role is unknown. PfRh1 and PfRh4, members of this protein family, bind to red blood cells and function in merozoite invasion during which they undergo a series of proteolytic cleavage events before and during entry into the host cell. The ectodomain of PfRh1 and PfRh4 are processed to produce fragments consistent with cleavage in the transmembrane domain and released into the supernatant, at about the time of invasion, in a manner consistent with rhomboid protease cleavage. Processing of both PfRh1 and PfRh4, and by extrapolation all membrane-bound members of this protein family, is important for function and release of these proteins on the merozoite surface and they along with EBA-175 are important components of the tight junction, the transient structure that links the erythrocyte via receptor–ligand interactions to the actin–myosin motor in the invading merozoite.
Highlights
Plasmodium falciparum causes the most severe form of malaria in humans and results in approximately 500 million infections and over two million deaths each year (Snow et al, 2005)
It is known that members of the PfRh protein family such as PfRh1 are proteolytically processed it is not known when these events occur during the invasion process (Triglia et al, 2005). We address these questions and show that PfRh1 and PfRh4 undergo a series of proteolytic cleavage events resulting in a number of fragments with the final event occurring within the transmembrane domain, most likely as a result of cleavage with P. falciparum rhomboid 4 (PfROM4), at the point of invasion resulting in shedding of a domain into the supernatant
We provide evidence that PfRh1 is most likely located within the tight junction and this protein family plays a key role in merozoite invasion
Summary
Plasmodium falciparum causes the most severe form of malaria in humans and results in approximately 500 million infections and over two million deaths each year (Snow et al, 2005). The invasive merozoite forms are released from mature schizont stages and these rapidly invade new red blood cells in a process mediated by a cascade of events that includes multiple receptor–ligand interactions (see for review Cowman and Crabb, 2006). The tight junction is propelled progressively along the surface of the invading merozoite by virtue of the force generated by the motor until membrane fusion at the posterior end of the parasite resulting in internalization within a parasitophorous vacuole. This invasion process is tightly controlled and completed within approximately 20–30 s
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