The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites.
3-Phosphoinositide-Dependent Protein Kinases
/ genetics
Animals
Catalytic Domain
Cell Line
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
/ metabolism
Cyclic AMP-Dependent Protein Kinases
/ genetics
Erythrocytes
/ parasitology
Humans
Malaria
Malaria, Falciparum
/ parasitology
Merozoites
Parasites
/ metabolism
Plasmodium falciparum
/ metabolism
Protozoan Proteins
/ metabolism
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
24
06
2021
accepted:
12
11
2021
revised:
20
12
2021
pubmed:
9
12
2021
medline:
4
1
2022
entrez:
8
12
2021
Statut:
epublish
Résumé
Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signalling is essential for the proliferation of Plasmodium falciparum malaria blood stage parasites. The mechanisms regulating the activity of the catalytic subunit PfPKAc, however, are only partially understood, and PfPKAc function has not been investigated in gametocytes, the sexual blood stage forms that are essential for malaria transmission. By studying a conditional PfPKAc knockdown (cKD) mutant, we confirm the essential role for PfPKAc in erythrocyte invasion by merozoites and show that PfPKAc is involved in regulating gametocyte deformability. We furthermore demonstrate that overexpression of PfPKAc is lethal and kills parasites at the early phase of schizogony. Strikingly, whole genome sequencing (WGS) of parasite mutants selected to tolerate increased PfPKAc expression levels identified missense mutations exclusively in the gene encoding the parasite orthologue of 3-phosphoinositide-dependent protein kinase-1 (PfPDK1). Using targeted mutagenesis, we demonstrate that PfPDK1 is required to activate PfPKAc and that T189 in the PfPKAc activation loop is the crucial target residue in this process. In summary, our results corroborate the importance of tight regulation of PfPKA signalling for parasite survival and imply that PfPDK1 acts as a crucial upstream regulator in this pathway and potential new drug target.
Identifiants
pubmed: 34879056
doi: 10.1371/journal.pbio.3001483
pii: PBIOLOGY-D-21-01680
pmc: PMC8687544
doi:
Substances chimiques
Protozoan Proteins
0
3-Phosphoinositide-Dependent Protein Kinases
EC 2.7.11.1
PDPK1 protein, human
EC 2.7.11.1
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
EC 2.7.11.11
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001483Subventions
Organisme : Medical Research Council
ID : MR/N009274/1
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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