Abstract
The malaria parasite Plasmodium falciparum traffics the virulence protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer's clefts. We developed a method for efficient enrichment of Maurer's clefts and profiled the protein composition of this trafficking organelle. We identified 13 previously uncharacterized or poorly characterized Maurer's cleft proteins. We generated transfectants expressing green fluorescent protein (GFP) fusions of 7 proteins and confirmed their Maurer's cleft location. Using co-immunoprecipitation and mass spectrometry, we generated an interaction map of proteins at the Maurer's clefts. We identified two key clusters that may function in the loading and unloading of PfEMP1 into and out of the Maurer's clefts. We focus on a putative PfEMP1 loading complex that includes the protein GEXP07/CX3CL1-binding protein 2 (CBP2). Disruption of GEXP07 causes Maurer's cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression, and loss of the PfEMP1-mediated adhesion. ΔGEXP07 parasites have a growth advantage compared to wild-type parasites, and the infected RBCs are more deformable and more osmotically fragile.IMPORTANCE The trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite-infected RBCs are central to severe adhesion-related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurer's clefts controlling PfEMP1 loading and unloading. We characterize a protein needed for virulence protein trafficking and provide new insights into the mechanisms for host cell remodeling, parasite survival within the host, and virulence.
Highlights
The malaria parasite Plasmodium falciparum traffics the virulence protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer’s clefts
The current model suggests that PfEMP1 is trafficked to Maurer’s clefts as a soluble, chaperoned complex (6, 7), where it is inserted into the membrane bilayer (8) before repackaging for vesicle-mediated trafficking to the RBC surface (9)
Maurer’s clefts are parasitederived membrane-bound structures that remain mobile within the RBC cytoplasm until ϳ20 h post invasion
Summary
The malaria parasite Plasmodium falciparum traffics the virulence protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer’s clefts. In the asexual blood stage of infection, parasites invade red blood cells (RBCs) and develop through the so-called ring, trophozoite (growing), and schizont (dividing) stages, eventually releasing invasive merozoites that continue the blood cycle During this cycle, the parasite induces marked changes to the host RBC, including the elaboration of new organelles in the RBC cytoplasm, known as the Maurer’s clefts (MC), and the establishment of protrusions at the RBC membrane, known as knobs. The knob acts as a scaffold for the presentation of the major virulence antigen P. falciparum erythrocyte membrane protein 1 (PfEMP1) This virulence complex has an important role in adhesion of infected RBCs to endothelial cell receptors. There is very limited information about interactions between proteins of the Maurer’s clefts and their virulence-associated cargo (15, 16)
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