title: Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite.
abstract: Apicomplexan pathogens are obligate intracellular parasites. To enter cells, they must bind with high affinity to host cell receptors and then uncouple these interactions to complete invasion. Merozoites of Plasmodium falciparum, the parasite responsible for the most dangerous form of malaria, invade erythrocytes using a family of adhesins called Duffy binding ligand-erythrocyte binding proteins (DBL-EBPs). The best-characterized P. falciparum DBL-EBP is erythrocyte binding antigen 175 (EBA-175), which binds erythrocyte surface glycophorin A. We report that EBA-175 is shed from the merozoite at around the point of invasion. Shedding occurs by proteolytic cleavage within the transmembrane domain (TMD) at a site that is conserved across the DBL-EBP family. We show that EBA-175 is cleaved by PfROM4, a rhomboid protease that localizes to the merozoite plasma membrane, but not by other rhomboids tested. Mutations within the EBA-175 TMD that abolish cleavage by PfROM4 prevent parasite growth. Our results identify a crucial role for intramembrane proteolysis in the life cycle of this pathogen.
authors.affiliation: Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, England, UK.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: O'Donnell
authors.forename: Fiona
authors.initials: F
authors.lastname: Hackett
authors.forename: Steven A
authors.initials: SA
authors.lastname: Howell
authors.forename: Moritz
authors.initials: M
authors.lastname: Treeck
authors.forename: Nicole
authors.initials: N
authors.lastname: Struck
authors.forename: Zita
authors.initials: Z
authors.lastname: Krnajski
authors.forename: Chrislaine
authors.initials: C
authors.lastname: Withers-Martinez
authors.forename: Tim W
authors.initials: TW
authors.lastname: Gilberger
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D004910:Erythrocyte Membrane / Q000469:parasitology*; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006790:Host-Parasite Interactions / Q000502:physiology; D006801:Humans; D008024:Ligands; D008288:Malaria / Q000469:parasitology*; D009154:Mutation; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology
chemical_list: D000953:Antigens, Protozoan; D008024:Ligands; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C065668:erythrocyte-binding antigen 175, Plasmodium; D010447:Peptide Hydrolases; C514390:ROM4 protein, Plasmodium falciparum