title: Ca(2+) -mediated exocytosis of subtilisin-like protease 1: a key step in egress of Plasmodium falciparum merozoites.
abstract: Egress of Plasmodium falciparum merozoites from host erythrocytes is a critical step in multiplication of blood-stage parasites. A cascade of proteolytic events plays a major role in degradation of membranes leading to egress of merozoites. However, the signals that regulate the temporal activation and/or secretion of proteases upon maturation of merozoites in intra-erythrocytic schizonts remain unclear. Here, we have tested the role of intracellular Ca(2+) in regulation of egress of P. falciparum merozoites from schizonts. A sharp rise in intracellular Ca(2+) just before egress, observed by time-lapse video microscopy, suggested a role for intracellular Ca(2+) in this process. Chelation of intracellular Ca(2+) with chelators such as BAPTA-AM or inhibition of Ca(2+) release from intracellular stores with a phospholipase C (PLC) inhibitor blocks merozoite egress. Interestingly, chelation of intracellular Ca(2+) in schizonts was also found to block the discharge of a key protease PfSUB1 (subtilisin-like protease 1) from exonemes of P. falciparum merozoites to parasitophorous vacuole (PV). This leads to inhibition of processing of PfSERA5 (serine repeat antigen 5) and a block in parasitophorous vacuolar membrane (PVM) rupture and merozoite egress. A complete understanding of the steps regulating egress of P. falciparum merozoites may provide novel targets for development of drugs that block egress and limit parasite growth.
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology ICGEB, New Delhi, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Agarwal
authors.forename: Maneesh Kumar
authors.initials: MK
authors.lastname: Singh
authors.forename: Swati
authors.initials: S
authors.lastname: Garg
authors.forename: Chetan E
authors.initials: CE
authors.lastname: Chitnis
authors.forename: Shailja
authors.initials: S
authors.lastname: Singh
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000469:parasitology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology* / Q000473:pathology; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D016778:Malaria, Falciparum; D052940:Merozoites / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018715:Microscopy, Video; D010963:Plasmodium falciparum / Q000472:pathogenicity* / Q000502:physiology; D015800:Protozoan Proteins / Q000502:physiology*; D013381:Subtilisins / Q000502:physiology*
chemical_list: D002614:Chelating Agents; D015800:Protozoan Proteins; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D013381:Subtilisins; C403176:subtilisin-like protease 1, Plasmodium falciparum; D002118:Calcium