title: Erythrocytic casein kinase II regulates cytoadherence of Plasmodium falciparum-infected red blood cells.
abstract: Plasmodium falciparum malaria is a major human health scourge and a key cause of mortality. Its pathogenicity partly results from the phenomenon of "cytoadherence" mediated by the PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1) family. Extracellular domains of PfEMP1s are variable and bind various host endothelial receptors, whereas their cytoplasmic domains (VARCs) are relatively conserved. VARCs affix PfEMP1s in the human erythrocyte membrane by interacting with host cytoskeleton proteins and exported parasite proteins. Here, we provide in vitro and in vivo evidence for PfEMP1 phosphorylation (on VARC) and propose an important function for this modification. Specific inhibitors and enhancers have been used to identify erythrocytic casein kinase II (CKII) as the enzyme responsible for VARC modification activity. We have also delineated probable CKII target residues on VARC, which mainly reside in an N-terminal acidic cluster. Our data show that VARC phosphorylation alters its binding to parasite encoded knob-associated histidine-rich protein (KAHRP). Finally, we demonstrate reduced cytoadherence of infected RBCs to endothelial receptors like ICAM-1 and CSA (these contribute to cerebral and placental malaria, respectively) in response to their CKII inhibition. Collectively, this study furthers our understanding of VARC function, underscores the importance of erythrocytic CKII in cytoadherence, and suggests a possible new target for anti-cytoadherence molecules.
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Rachna
authors.initials: R
authors.lastname: Hora
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bridges
authors.forename: Alister
authors.initials: A
authors.lastname: Craig
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D002448:Cell Adhesion; D004912:Erythrocytes / Q000201:enzymology* / Q000469:parasitology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016778:Malaria, Falciparum / Q000201:enzymology*; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D018799:Intercellular Adhesion Molecule-1; D047390:Casein Kinase II