Abstract
Protein export into the host red blood cell is one of the key processes in the pathobiology of the malaria parasite Plasmodiumtrl falciparum, which extensively remodels the red blood cell to ensure its virulence and survival. In this study, we aimed to shed further light on the protein export mechanisms in the rodent malaria parasite P. berghei and provide further proof of the conserved nature of host cell remodeling in Plasmodium spp. Based on the presence of an export motif (R/KxLxE/Q/D) termed PEXEL (Plasmodium export element), we have generated transgenic P. berghei parasite lines expressing GFP chimera of putatively exported proteins and analysed one of the newly identified exported proteins in detail. This essential protein, termed PbCP1 (P. berghei Cleft-like Protein 1), harbours an atypical PEXEL motif (RxLxY) and is further characterised by two predicted transmembrane domains (2TMD) in the C-terminal end of the protein. We have functionally validated the unusual PEXEL motif in PbCP1 and analysed the role of the 2TMD region, which is required to recruit PbCP1 to discrete membranous structures in the red blood cell cytosol that have a convoluted, vesico-tubular morphology by electron microscopy. Importantly, this study reveals that rodent malaria species also induce modifications to their host red blood cell.
Highlights
The human malaria parasite Plasmodium falciparum exports approximately three hundred proteins into its host red blood cell (RBC) [1] leading to a number of morphological alterations to the cell such as increased rigidity and adhesiveness
All ten candidates are encoded by two exons, a common feature shared amongst many P. falciparum exported proteins [1], and are characterised by the presence of a signal peptide or a hydrophobic stretch in the Nterminus upstream of the PEXEL motif [9,10] (Table S1)
Protein export is crucial to the virulence and survival of malaria parasites, investigations into the mechanisms behind protein export are of great importance as these pathways provide excellent targets for drug intervention
Summary
The human malaria parasite Plasmodium falciparum exports approximately three hundred proteins into its host red blood cell (RBC) [1] leading to a number of morphological alterations to the cell such as increased rigidity and adhesiveness (for review, see [2]). Parasite-induced membranous structures appear in the host cell cytoplasm, including the Maurer’s clefts, which have been implicated to be involved in sorting and trafficking of virulence proteins (for reviews, see [6,7]) and the HSP40-containing J-dots [8]. These alterations to the RBC enable the pathogen to resist the febrile episodes of the host and to acquire nutrients from the host serum, they facilitate adherence of the infected RBC (iRBC) to the vascular endothelium, allowing the parasite to avoid immune clearance, and securing the survival of the parasite. Passage of most exported proteins across the parasite-host cell interface is mediated by a pentameric amino acid motif
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