title: Targeted mutagenesis of Plasmodium falciparum erythrocyte membrane protein 3 (PfEMP3) disrupts cytoadherence of malaria-infected red blood cells.
abstract: Adhesion of parasite-infected red blood cells to the vascular endothelium is a critical event in the pathogenesis of malaria caused by Plasmodium falciparum. Adherence is mediated by the variant erythrocyte membrane protein 1 (PfEMP1). Another protein, erythrocyte membrane protein-3 (PfEMP3), is deposited under the membrane of the parasite-infected erythrocyte but its function is unknown. Here we show that mutation of PfEMP3 disrupts transfer of PfEMP1 to the outside of the P.FALCIPARUM:-infected cell. Truncation of the C-terminal end of PfEMP3 by transfection prevents distribution of this large (>300 kDa) protein around the membrane but does not disrupt trafficking of the protein from the parasite to the cytoplasmic face of the erythrocyte membrane. The truncated PfEMP3 accumulates in structures that appear to be associated with the erythrocyte membrane. We show that accumulation of mutated PfEMP3 blocks the transfer of PfEMP1 onto the outside of the parasitized cell surface and suggest that these proteins traffic through an erythrocyte membrane-associated compartment that is involved in the transfer of PfEMP1 to the surface of the parasite-infected red blood cell.
authors.affiliation: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Department of Pathology, The University of Melbourne, Melbourne 3050, Australia.
authors.forename: J G
authors.initials: JG
authors.lastname: Waterkeyn
authors.forename: M E
authors.initials: ME
authors.lastname: Wickham
authors.forename: K M
authors.initials: KM
authors.lastname: Davern
authors.forename: B M
authors.initials: BM
authors.lastname: Cooke
authors.forename: R L
authors.initials: RL
authors.lastname: Coppel
authors.forename: J C
authors.initials: JC
authors.lastname: Reeder
authors.forename: J G
authors.initials: JG
authors.lastname: Culvenor
authors.forename: R F
authors.initials: RF
authors.lastname: Waller
authors.forename: A F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D002451:Cell Compartmentation; D016764:Cell Polarity; D004730:Endothelium, Vascular / Q000469:parasitology; D004910:Erythrocyte Membrane / Q000469:parasitology* / Q000648:ultrastructure; D017125:Genes, Protozoan; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D016296:Mutagenesis; D010455:Peptides / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics* / Q000648:ultrastructure; D015800:Protozoan Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: D018955:CD36 Antigens; C411566:EMP3 protein, Plasmodium falciparum; D008565:Membrane Proteins; D010455:Peptides; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; C042968:knob protein, Plasmodium falciparum