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

Hanwei Fang, Ana Rita Gomes, Natacha Klages, Paco Pino, Bohumil Maco, Eloise M. Walker, Zenon A. Zenonos, Fiona Angrisano, Jake Baum, Christian Doerig, David A. Baker, Oliver Billker and Mathieu Brochet ()
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Hanwei Fang: University of Geneva
Ana Rita Gomes: Wellcome Trust Sanger Institute
Natacha Klages: University of Geneva
Paco Pino: University of Geneva
Bohumil Maco: University of Geneva
Eloise M. Walker: London School of Hygiene &Tropical Medicine
Zenon A. Zenonos: Wellcome Trust Sanger Institute
Fiona Angrisano: Imperial College London
Jake Baum: Imperial College London
Christian Doerig: Monash University
David A. Baker: London School of Hygiene &Tropical Medicine
Oliver Billker: Umeå University
Mathieu Brochet: University of Geneva

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06733-w

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