title: Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress.
abstract: The malaria parasite replicates within an intraerythrocytic parasitophorous vacuole (PV). Eventually, in a tightly regulated process called egress, proteins of the PV and intracellular merozoite surface are modified by an essential parasite serine protease called PfSUB1, whilst the enclosing PV and erythrocyte membranes rupture, releasing merozoites to invade fresh erythrocytes. Inhibition of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) prevents egress, but the underlying mechanism is unknown. Here we show that PfPKG activity is required for PfSUB1 discharge into the PV, as well as for release of distinct merozoite organelles called micronemes. Stimulation of PfPKG by inhibiting parasite phosphodiesterase activity induces premature PfSUB1 discharge and egress of developmentally immature, non-invasive parasites. Our findings identify the signalling pathway that regulates PfSUB1 function and egress, and raise the possibility of targeting PfPKG or parasite phosphodiesterases in therapeutic approaches to dysregulate critical protease-mediated steps in the parasite life cycle.
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Collins
authors.forename: Fiona
authors.initials: F
authors.lastname: Hackett
authors.forename: Malcolm
authors.initials: M
authors.lastname: Strath
authors.forename: Maria
authors.initials: M
authors.lastname: Penzo
authors.forename: Chrislaine
authors.initials: C
authors.lastname: Withers-Martinez
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
mesh_terms: D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006790:Host-Parasite Interactions / Q000502:physiology*; D052940:Merozoites / Q000502:physiology*; D015388:Organelles / Q000378:metabolism; D010963:Plasmodium falciparum / Q000502:physiology*; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015800:Protozoan Proteins; D017869:Cyclic GMP-Dependent Protein Kinases