Delivery of the Malaria Virulence Protein PfEMP1 to the Erythrocyte Surface Requires Cholesterol-Rich Domains

doi:10.1128/EC.5.5.849-860.2006

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Delivery of the Malaria Virulence Protein PfEMP1 to the Erythrocyte Surface Requires Cholesterol-Rich Domains

Sarah Frankland,¹^,2 Akinola Adisa,¹ Paul Horrocks,³ Theodore F. Taraschi,⁴ Timothy Schneider,⁴ Salenna R. Elliott,⁵ Stephen J. Rogerson,⁵ Ellen Knuepfer,⁶ Alan F. Cowman,⁶ Chris I. Newbold,³ and Leann Tilley¹^,2^*

Department of Biochemistry,¹ Cooperative Research Centre for Vaccine Technology, La Trobe University, Melbourne 3086, Australia,² Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom,³ Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,⁴ Department of Medicine, University of Melbourne, Post Office Royal Melbourne Hospital, Parkville 3050, Australia,⁵ The Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia⁶

Received 30 October 2005/ Accepted 27 December 2005

The particular virulence of the human malaria parasite Plasmodiumfalciparum derives from export of parasite-encoded proteinsto the surface of the mature erythrocytes in which it resides.The mechanisms and machinery for the export of proteins to theerythrocyte membrane are largely unknown. In other eukaryoticcells, cholesterol-rich membrane microdomains or "rafts" havebeen shown to play an important role in the export of proteinsto the cell surface. Our data suggest that depletion of cholesterolfrom the erythrocyte membrane with methyl-ß-cyclodextrinsignificantly inhibits the delivery of the major virulence factorP. falciparum erythrocyte membrane protein 1 (PfEMP1). The traffickingdefect appears to lie at the level of transfer of PfEMP1 fromparasite-derived membranous structures within the infected erythrocytecytoplasm, known as the Maurer's clefts, to the erythrocytemembrane. Thus our data suggest that delivery of this key cytoadherence-mediatingprotein to the host erythrocyte membrane involves insertionof PfEMP1 at cholesterol-rich microdomains. GTP-dependent vesiclebudding and fusion events are also involved in many traffickingprocesses. To determine whether GTP-dependent events are involvedin PfEMP1 trafficking, we have incorporated non-membrane-permeatingGTP analogs inside resealed erythrocytes. Although these nonhydrolyzableGTP analogs reduced erythrocyte invasion efficiency and partiallyretarded growth of the intracellular parasite, they appearedto have little direct effect on PfEMP1 trafficking.

* Corresponding author. Mailing address: Department of Biochemistry, La Trobe University, Melbourne 3086, Australia. Phone: 61-3-94791375. Fax: 61-3-94792467. E-mail: L.Tilley{at}LaTrobe.edu.au.

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