Ectophosphorylation of CD36 Regulates Cytoadherence of Plasmodium falciparum to Microvascular Endothelium under Flow Conditions

The adhesion of Plasmodium falciparum-infected erythrocytes (IRBCs) to human dermal microvascular endothelial cells (HDMECs) under flow conditions is regulated by a Src family kinase- and alkaline phosphatase (AP)-dependent mechanism. In this study, we showed that the target of the phosphatase activ...

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Published in:	Infection and Immunity Vol. 73; no. 12; pp. 8179 - 8187
Main Authors:	Ho, May, Hoang, Holly L, Lee, Kristine M, Liu, Naili, MacRae, Tara, Montes, Laura, Flatt, Christine L, Yipp, Bryan G, Berger, Bradley J, Looareesuwan, Sorrnchai, Robbins, Stephen M
Format:	Journal Article
Language:	English
Published:	Washington, DC American Society for Microbiology 01-12-2005
Subjects:	Alkaline Phosphatase - analysis Alkaline Phosphatase - metabolism Animals Antibodies, Phospho-Specific - pharmacology Biological and medical sciences Capillaries - cytology CD36 Antigens - analysis CD36 Antigens - genetics CD36 Antigens - metabolism Cell Adhesion - drug effects Cellular Microbiology: Pathogen-Host Cell Molecular Interactions Endothelium, Vascular - immunology Erythrocytes - parasitology Fundamental and applied biological sciences. Psychology Humans Levamisole - pharmacology Mice Microbiology Mutation NIH 3T3 Cells Phosphorylation Plasmodium falciparum Plasmodium falciparum - pathogenicity Protein Structure, Tertiary Pyrazoles - pharmacology Pyrimidines - pharmacology Skin - blood supply src-Family Kinases - antagonists & inhibitors src-Family Kinases - metabolism Threonine - genetics Threonine - metabolism Protozoa Plasmodium falciparum Apicomplexa Regulation(control) Microbiology Immunity Endothelium
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Summary:	The adhesion of Plasmodium falciparum-infected erythrocytes (IRBCs) to human dermal microvascular endothelial cells (HDMECs) under flow conditions is regulated by a Src family kinase- and alkaline phosphatase (AP)-dependent mechanism. In this study, we showed that the target of the phosphatase activity is the ectodomain of CD36 at threonine-92 (Thr⁹²). Mouse fibroblasts (NIH 3T3 cells) transfected with wild-type CD36 or a mutant protein in which Thr⁹² was substituted by Ala supported the rolling and adhesion of IRBCs. However, while the Src family kinase inhibitors PP1 and PP2 and the specific AP inhibitor levamisole significantly reduced IRBC adhesion to wild-type CD36 transfectants as with HDMECs, the inhibitors had no effect on IRBC adhesion to the mutant cells. Using a phosphospecific antibody directed at a 12-amino-acid peptide spanning Thr⁹², we demonstrated directly that CD36 was constitutively phosphorylated and could be dephosphorylated by exogenous AP. Endothelial CD36 was likewise constitutively phosphorylated. The phosphospecific antibody inhibited IRBC adhesion to HDMECs that could be reversed by preincubating the antibody with the phosphorylated but not the nonphosphorylated peptide. Pretreatment of HDMECs with AP abrogated the effect of PP1 on IRBC adhesion. Collectively, these results are consistent with a critical role for CD36 dephosphorylation through Src family kinase activation in regulating IRBC adhesion to vascular endothelium.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Editor: J. F. Urban, Jr. Corresponding author. Mailing address: Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1 Canada. Phone: (403) 220-8516. Fax: (403) 270-8520. E-mail: mho@ucalgary.ca.
ISSN:	0019-9567 1098-5522
DOI:	10.1128/IAI.73.12.8179-8187.2005