Abstract
Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). A recent study reported that phosphatidylinositol-3-phosphate (PI(3)P) concentrated in the ER binds to PEXEL motifs and is required for export independent of PMV, and that PEXEL motifs are functionally interchangeable with RxLR motifs of oomycete effectors. Here we show that the PEXEL does not bind PI(3)P, and that this lipid is not concentrated in the ER. We find that RxLR motifs cannot mediate export in P. falciparum. Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage. This mutant possessed the putative PI(3)P-binding residues but is not exported. Reinstatement of PEXEL to its original location restores processing by PMV and export. These results challenge the PI(3)P hypothesis and provide evidence that PEXEL position is conserved for co-translational processing and export.
Highlights
Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV)
Bhattacharjee et al.[24,25,45] have suggested the PEXEL directs export by binding to PI(3)P on the inner ER leaflet, and that the RxLR motif of P. infestans can functionally replace PEXEL. They showed RxLR was not cleaved by PMV and concluded export of PEXEL proteins occurs independent of this enzyme
We show PEXEL proteins and PfEMP1 do not bind PI(3)P, that this lipid is not present inside the ER, and that RxLR cannot functionally complement the PEXEL in P. falciparum
Summary
Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage This mutant possessed the putative PI(3)P-binding residues but is not exported. Remodelling results in profound structural and morphological changes of the host cell central to parasite survival This includes alterations of the cells physical properties, making it more rigid and gaining adhesive properties that can block flow in the microvasculature[2,3]. We find PEXEL does not bind PI(3)P, this phospholipid is not concentrated in the ER of P. falciparum but on the food vacuole and apicoplast membranes, that the PEXEL is not functionally interchangeable with the RxLR motif of oomycetes and the PEXEL is located at a conserved location to ensure co-translational processing by PMV for export. PI(3)P binding of PEXEL in the ER is not the selective mechanism for export of malarial effector proteins to the P. falciparum-infected erythrocyte
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