Virulence determinant, PTP7, controls vesicle budding from the Maurer’s clefts, adhesin protein trafficking and host cell remodeling in Plasmodium falciparum

Presentation of the variant antigen, Plasmodium falciparum erythrocyte membrane protein 1 (EMP1), at knob-like protrusions on the surface of infected red blood cells, underpins P. falciparum malaria pathogenicity. Here we describe a protein PF3D7_0301700 (PTP7), that functions at the nexus between the intermediate trafficking organelle, the Maurer’s cleft, and the red blood cell surface. Genetic disruption of PTP7 leads to accumulation of vesicles at the Maurer’s clefts, grossly aberrant knob morphology, and failure to deliver EMP1 to the red blood cell surface. We show that an expanded low complexity sequence in the C-terminal region of PTP7, found only in the Laverania clade of Plasmodium , is critical for efficient virulence protein trafficking.

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The Cytoplasmic Region of Plasmodium falciparum SURFIN4.2 Is Required for Transport from Maurer’s Clefts to the Red Blood Cell Surface

Tropical Medicine and Health ◽

10.2149/tmh.2015-38 ◽

2015 ◽

Vol 43 (4) ◽

pp. 265-272 ◽

Cited By ~ 5

Author(s):

Wataru Kagaya ◽

Shinya Miyazaki ◽

Kazuhide Yahata ◽

Nobuo Ohta ◽

Osamu Kaneko

Keyword(s):

Plasmodium Falciparum ◽

Cell Surface ◽

Blood Cell ◽

Red Blood Cell ◽

Cytoplasmic Region ◽

Maurer's Clefts

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Antibodies in children with malaria to PfEMP1, RIFIN and SURFIN expressed at the Plasmodium falciparum parasitized red blood cell surface

Scientific Reports ◽

10.1038/s41598-018-21026-4 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 3

Author(s):

Maria del Pilar Quintana ◽

Jun-Hong Ch’ng ◽

Kirsten Moll ◽

Arash Zandian ◽

Peter Nilsson ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Cell Surface ◽

Blood Cell ◽

Red Blood Cell

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Serum Lipoproteins Promote Efficient Presentation of the Malaria Virulence Protein PfEMP1 at the Erythrocyte Surface

Eukaryotic Cell ◽

10.1128/ec.00063-07 ◽

2007 ◽

Vol 6 (9) ◽

pp. 1584-1594 ◽

Cited By ~ 31

Author(s):

Sarah Frankland ◽

Salenna R. Elliott ◽

Francisca Yosaatmadja ◽

James G. Beeson ◽

Stephen J. Rogerson ◽

...

Keyword(s):

Cell Surface ◽

Blood Cell ◽

Erythrocyte Membrane ◽

Red Blood Cell ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Bathing Medium ◽

Virulence Protein ◽

Adhesive Proteins ◽

Serum Components

ABSTRACT The virulence of the malaria parasite Plasmodium falciparum is related to its ability to express a family of adhesive proteins known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) at the infected red blood cell surface. The mechanism for the transport and delivery of these adhesins to the erythrocyte membrane is only poorly understood. In this work, we have used specific immune reagents in a flow cytometric assay to monitor the effects of serum components on the surface presentation of PfEMP1. We show that efficient presentation of the A4 and VAR2CSA variants of PfEMP1 is dependent on the presence of serum in the bathing medium during parasite maturation. Lipid-loaded albumin supports parasite growth but allows much less efficient presentation of PfEMP1 at the red blood cell surface. Analysis of the serum components reveals that lipoproteins, especially those of the low-density lipoprotein fraction, promote PfEMP1 presentation. Cytoadhesion of infected erythrocytes to the host cell receptors CD36 and ICAM-1 is also decreased in infected erythrocytes cultured in the absence of serum. The defect appears to be in the transfer of PfEMP1 from parasite-derived structures known as the Maurer's clefts to the erythrocyte membrane or in surface conformation rather than a down-regulation or switching of particular PfEMP1 variants.

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PEXEL-independent trafficking of Plasmodium falciparum SURFIN4.2 to the parasite-infected red blood cell and Maurer's clefts

Parasitology International ◽

10.1016/j.parint.2011.05.003 ◽

2011 ◽

Vol 60 (3) ◽

pp. 313-320 ◽

Cited By ~ 18

Author(s):

Jean Semé Fils Alexandre ◽

Kazuhide Yahata ◽

Satoru Kawai ◽

Motomi Torii ◽

Osamu Kaneko

Keyword(s):

Plasmodium Falciparum ◽

Blood Cell ◽

Red Blood Cell ◽

Maurer's Clefts

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Maurer's clefts of Plasmodium falciparum are secretory organelles that concentrate virulence protein reporters for delivery to the host erythrocyte

Blood ◽

10.1182/blood-2007-09-115279 ◽

2008 ◽

Vol 111 (4) ◽

pp. 2418-2426 ◽

Cited By ~ 54

Author(s):

Souvik Bhattacharjee ◽

Christiaan van Ooij ◽

Bharath Balu ◽

John H. Adams ◽

Kasturi Haldar

Keyword(s):

Plasmodium Falciparum ◽

Protein Trafficking ◽

Parasite Protein ◽

Human Malaria Parasite ◽

Parasite Plasmodium ◽

Virulence Protein ◽

Parasite Plasmodium Falciparum ◽

Blood Stage Infection ◽

Maurer's Clefts ◽

Stage Infection

In blood-stage infection by the human malaria parasite Plasmodium falciparum, export of proteins from the intracellular parasite to the erythrocyte is key to virulence. This export is mediated by a host-targeting (HT) signal present on a “secretome” of hundreds of parasite proteins engaged in remodeling the erythrocyte. However, the route of HT-mediated export is poorly understood. Here we show that minimal soluble and membrane protein reporters that contain the HT motif and mimic export of endogenous P falciparum proteins are detected in the lumen of “cleft” structures synthesized by the pathogen. Clefts are efficiently targeted by the HT signal. Furthermore, the HT signal does not directly translocate across the parasitophorous vacuolar membrane (PVM) surrounding the parasite to deliver protein to the erythrocyte cytoplasm, as suggested by current models of parasite protein trafficking to the erythrocyte. Rather, it is a lumenal signal that sorts protein into clefts, which then are exported beyond the PVM. These data suggest that Maurer's clefts, which are unique to the virulent P falciparum species, are pathogen-induced secretory organelles that concentrate HT-containing soluble and membrane parasite proteins in their lumen for delivery to the host erythrocyte.

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The Plasmodium falciparum protein VCAP1 controls Maurer’s cleft morphology, knob architecture and PfEMP1 trafficking

10.1101/741033 ◽

2019 ◽

Author(s):

Emma McHugh ◽

Olivia Carmo ◽

Adam Blanch ◽

Oliver Looker ◽

Boyin Liu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Protein Interaction ◽

Protein Trafficking ◽

Placental Malaria ◽

Protein Composition ◽

Surface Expression ◽

Virulence Protein ◽

Infected Rbcs ◽

Loading And Unloading ◽

Maurer's Clefts

AbstractThe 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 uncharacterised or poorly characterised Maurer’s cleft proteins. We generated transfectants expressing GFP-fusions of 7 proteins and confirmed their Maurer’s cleft location. Using co-immunoprecipitation and mass spectrometry we have generated a protein 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 newly characterised virulence complex assembly protein 1 (VCAP1). Disruption of VCAP1 causes Maurer’s cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression and loss of the PfEMP1 directed adhesion. ΔVCAP1 parasite lines have a growth advantage compared to wildtype parasites; and the infected RBCs are more deformable and more osmotically fragile.ImportanceThe trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite infected RBCs is 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. This work adds significantly to our understanding of virulence protein trafficking and will provide crucial knowledge that will be required to determine the mechanisms underpinning parasite driven host cell remodelling, parasite survival within the host and virulence mechanisms.

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