Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes.
The most virulent form of malaria is caused by waves of replication of blood stages of the protozoan pathogen Plasmodium falciparum. The parasite divides within an intraerythrocytic parasitophorous vacuole until rupture of the vacuole and host-cell membranes releases merozoites that invade fresh erythrocytes to repeat the cycle. Despite the importance of merozoite egress for disease progression, none of the molecular factors involved are known. We report that, just prior to egress, an essential serine protease called PfSUB1 is discharged from previously unrecognized parasite organelles (termed exonemes) into the parasitophorous vacuole space. There, PfSUB1 mediates the proteolytic maturation of at least two essential members of another enzyme family called SERA. Pharmacological blockade of PfSUB1 inhibits egress and ablates the invasive capacity of released merozoites. Our findings reveal the presence in the malarial parasitophorous vacuole of a regulated, PfSUB1-mediated proteolytic processing event required for release of viable parasites from the host erythrocyte.
Yeoh
Sharon
S
Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
O'Donnell
Rebecca A
RA
Koussis
Konstantinos
K
Dluzewski
Anton R
AR
Ansell
Keith H
KH
Osborne
Simon A
SA
Hackett
Fiona
F
Withers-Martinez
Chrislaine
C
Mitchell
Graham H
GH
Bannister
Lawrence H
LH
Bryans
Justin S
JS
Kettleborough
Catherine A
CA
Blackman
Michael J
MJ
D000818:Animals; D000953:Antigens, Protozoan / Q000378:metabolism / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology*; D006790:Host-Parasite Interactions; D008018:Life Cycle Stages; D008288:Malaria / Q000097:blood / Q000469:parasitology*; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000472:pathogenicity / Q000648:ultrastructure; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D034101:Sporozoites / Q000502:physiology; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D014617:Vacuoles / Q000469:parasitology
D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C480167:serine repeat antigen 5, Plasmodium falciparum; D013381:Subtilisins; C403176:subtilisin-like protease 1, Plasmodium falciparum