Erythrocytic Casein Kinase II Regulates Cytoadherence of Plasmodium falciparum-infected Red Blood Cells

Hora, R., Bridges, D. J., Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164 and Sharma, A. (2009) 'Erythrocytic Casein Kinase II Regulates Cytoadherence of Plasmodium falciparum-infected Red Blood Cells'. Journal of Biological Chemistry, Vol 284, Issue 10, pp. 6260-6269.

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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.

Item Type:	Article
Additional Information:	This research was originally published in Journal Name. R. Hora, D.J. Bridges, A. Craig, A Sharma. Erythrocytic Casein Kinase II Regulates Cytoadherence of Plasmodium falciparum-infected Red Blood Cells. Journal of Biological Chemistry. 2009; 284:6260-6269. © the American Society for Biochemistry and Molecular Biology. URL: http://www.jbc.org/content/284/10/6260.full.pdf+html
Uncontrolled Keywords:	histidine-rich protein membrane protein-1 subcellular-localization phosphorylation malaria pfemp1 ligand spectrin parasite receptor
Subjects:	QX Parasitology > Protozoa > QX 135 Plasmodia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria QX Parasitology > QX 45 Host-parasite relations
Faculty: Department:	Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Depositing User:	Mary Creegan
Date Deposited:	02 Jul 2010 09:10
Last Modified:	17 Jul 2020 10:57
URI:	https://archive.lstmed.ac.uk/id/eprint/286

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