Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress

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...

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Bibliographic Details
Published in:PLoS pathogens 2013-05, Vol.9 (5), p.e1003344-e1003344
Main Authors: Collins, Christine R, Hackett, Fiona, Strath, Malcolm, Penzo, Maria, Withers-Martinez, Chrislaine, Baker, David A, Blackman, Michael J
Format: Article
Language:English
Subjects:
Biology
Cellular control mechanisms
Cyclic GMP-Dependent Protein Kinases - metabolism
Cyclic guanylic acid
Enzyme-Linked Immunosorbent Assay
Fluorescent Antibody Technique
Host-Parasite Interactions - physiology
Kinases
Malaria
Medical research
Merozoites - physiology
Observations
Organelles - metabolism
Parasites
Parasitic diseases
Plasmodium falciparum - physiology
Properties
Protein kinases
Proteins
Protozoan Proteins - metabolism
Signal Transduction - physiology
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1003344