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Nat Commun. 2018 Oct 12;9(1):4248. doi: 10.1038/s41467-018-06733-w.

Epistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites.

Author information

1
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland.
2
Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
3
UMR 5290 Mivegec, University of Montpellier, Montpellier, 34295, France.
4
Faculty of Infectious and Tropical Diseases, London School of Hygiene &Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
5
Antibody Discovery and Protein Engineering, MedImmune, Cambridge, CB21 6GH, UK.
6
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
7
Department of Microbiology, Infection & Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
8
The Laboratory for Molecular Infection Medicine Sweden (MIMS), Department of Molecular Biology, Umeå University, Umeå, SE-901 87, Sweden.
9
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. Mathieu.Brochet@unige.ch.

Abstract

In malaria parasites, evolution of parasitism has been linked to functional optimisation. Despite this optimisation, most members of a calcium-dependent protein kinase (CDPK) family show genetic redundancy during erythrocytic proliferation. To identify relationships between phospho-signalling pathways, we here screen 294 genetic interactions among protein kinases in Plasmodium berghei. This reveals a synthetic negative interaction between a hypomorphic allele of the protein kinase G (PKG) and CDPK4 to control erythrocyte invasion which is conserved in P. falciparum. CDPK4 becomes critical when PKG-dependent calcium signals are attenuated to phosphorylate proteins important for the stability of the inner membrane complex, which serves as an anchor for the acto-myosin motor required for motility and invasion. Finally, we show that multiple kinases functionally complement CDPK4 during erythrocytic proliferation and transmission to the mosquito. This study reveals how CDPKs are wired within a stage-transcending signalling network to control motility and host cell invasion in malaria parasites.

PMID:
30315162
PMCID:
PMC6185908
DOI:
10.1038/s41467-018-06733-w
[Indexed for MEDLINE]
Free PMC Article

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