title: An exported kinase (FIKK4.2) that mediates virulence-associated changes in Plasmodium falciparum-infected red blood cells.
abstract: Alteration of the adhesive and mechanical properties of red blood cells caused by infection with the malaria parasite Plasmodium falciparum underpin both its survival and extreme pathogenicity. A unique family of parasite putative exported kinases, collectively called FIKK (Phenylalanine (F) - Isoleucine (I) - Lysine (K) - Lysine (K)), has recently been implicated in these pathophysiological processes, however, their precise function in P. falciparum-infected red blood cells or their likely role in malaria pathogenesis remain unknown. Here, for the first time, we demonstrate that one member of the FIKK family, FIKK4.2, can function as an active kinase and is localised in a novel and distinct compartment of the parasite-infected red blood cell which we have called K-dots. Notably, targeted disruption of the gene encoding FIKK4.2 (fikk4.2) dramatically alters the parasite's ability to modify and remodel the red blood cells in which it multiplies. Specifically, red blood cells infected with fikk4.2 knockout parasites were significantly less rigid and less adhesive when compared with red blood cells infected with normal parasites from which the transgenic clones had been derived, despite expressing similar levels of the major cytoadhesion ligand, PfEMP1, on the red blood cell surface. Notably, these changes were accompanied by dramatically altered knob-structures on infected red blood cells that play a key role in cytoadhesion which is responsible for much of the pathogenesis associated with falciparum malaria. Taken together, our data identifies FIKK4.2 as an important kinase in the pathogenesis of P. falciparum malaria and strengthens the attractiveness of FIKK kinases as targets for the development of novel next-generation anti-malaria drugs.
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Lev M
authors: LM
authors: Kats
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Kate M
authors: KM
authors: Fernandez
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Fiona K
authors: FK
authors: Glenister
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Susann
authors: S
authors: Herrmann
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Donna W
authors: DW
authors: Buckingham
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Ghizal
authors: G
authors: Siddiqui
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Laveena
authors: L
authors: Sharma
authors: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Rebecca
authors: R
authors: Bamert
authors: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
authors: Isabelle
authors: I
authors: Lucet
authors: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France; Centre National de la Recherche Scientifique, URA 2581, Paris, France.
authors: Micheline
authors: M
authors: Guillotte
authors: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France; Centre National de la Recherche Scientifique, URA 2581, Paris, France.
authors: Odile
authors: O
authors: Mercereau-Puijalon
authors: Department of Microbiology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia. Electronic address: brian.cooke@monash.edu.
authors: Brian M
authors: BM
authors: Cooke
mesh_terms: D004912:Erythrocytes / Q000469:parasitology*; D055786:Gene Knockout Techniques; D006801:Humans; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D021381:Protein Transport; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D037521:Virulence Factors; D010770:Phosphotransferases
keywords: Cell adhesion; Cell mechanics; Exported proteins; Kinases; Malaria; Plasmodium falciparum; Red blood cell