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An Exported Kinase Family Mediates Species-Specific Erythrocyte Remodelling and Virulence in Human Malaria

ABSTRACT: The most severe form of human malaria is caused by Plasmodium falciparum. Its virulence is closely linked to the increase in rigidity and cytoadhesion of infected erythrocytes, which obstruct blood flow to vital organs. Unlike other human-infecting Plasmodium species, P. falciparum exports a family of 18 ‘FIKK’ serine/threonine kinases into the host cell. We reveal substantial species-specific phosphorylation of erythrocyte proteins by P. falciparum, but not by Plasmodium knowlesi, which does not export FIKK kinases. By systematic deletion of all FIKK kinases combined with large-scale quantitative phosphoproteomics we identify unique phosphorylation fingerprints for each kinase, including phosphosites on parasite virulence factors and host cell proteins. Despite their non-overlapping target sites, a network analysis reveals that some FIKKs may act in the same pathways. Only deletion of the non-exported kinase FIKK8 resulted in reduced parasite growth, suggesting the exported FIKKs may support functions important for survival within the host. We show that one kinase, FIKK4.1, mediates both cytoskeletal rigidification and trafficking of the adhesin and key virulence factor PfEMP1 to the host cell surface. This establishes the FIKK family as important drivers of parasite evolution and malaria pathology.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Homo Sapiens (human) Plasmodium Falciparum (isolate 3d7) Plasmodium Knowlesi Strain H

TISSUE(S): Erythrocyte, Blood

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: Malgorzata Broncel

LAB HEAD: Moritz Treeck

PROVIDER: PXD015833 | Pride | 2020-04-17

REPOSITORIES: Pride

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An exported kinase family mediates species-specific erythrocyte remodelling and virulence in human malaria.

Davies Heledd H Belda Hugo H Broncel Malgorzata M Ye Xingda X Bisson Claudine C Introini Viola V Dorin-Semblat Dominique D Semblat Jean-Philippe JP Tibúrcio Marta M Gamain Benoit B Kaforou Myrsini M Treeck Moritz M Treeck Moritz M

Nature microbiology 20200413 6

The most severe form of human malaria is caused by Plasmodium falciparum. Its virulence is closely linked to the increase in rigidity of infected erythrocytes and their adhesion to endothelial receptors, obstructing blood flow to vital organs. Unlike other human-infecting Plasmodium species, P. falciparum exports a family of 18 FIKK serine/threonine kinases into the host cell, suggesting that phosphorylation may modulate erythrocyte modifications. We reveal substantial species-specific phosphory ...[more]

PMID: 32284562

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