A Maurer's cleft-associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells

doi:10.1083/jcb.200509122

Published online 6 March 2006. doi:10.1083/jcb.200509122
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 6, 899-908

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Article

A Maurer's cleft–associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells

Brian M. Cooke¹, Donna W. Buckingham¹, Fiona K. Glenister¹, Kate M. Fernandez¹, Lawrence H. Bannister³, Matthias Marti⁴, Narla Mohandas⁵, and Ross L. Coppel²

¹ Molecular and Cellular Rheology Laboratory, Department of Microbiology, and ² Department of Microbiology and Victorian Bioinformatics Consortium, Monash University, Victoria 3800, Australia
³ Wolfson Centre for Age-Related Diseases, Guy's, King's, and St. Thomas' Hospitals School of Biomedical and Health Sciences, Kings College London, London SE1 1UL, United Kingdom
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
⁵ New York Blood Center, New York, NY 10021

Correspondence to Brian M. Cooke: brian.cooke{at}med.monash.edu.au

The high mortality of Plasmodium falciparum malaria is the resultof a parasite ligand, PfEMP1 (P. falciparum) erythrocyte membraneprotein 1), on the surface of infected red blood cells (IRBCs),which adheres to the vascular endothelium and causes the sequestrationof IRBCs in the microvasculature. PfEMP1 transport to the IRBCsurface involves Maurer's clefts, which are parasite-derivedmembranous structures in the IRBC cytoplasm. Targeted gene disruptionof a Maurer's cleft protein, SBP1 (skeleton-binding protein1), prevented IRBC adhesion because of the loss of PfEMP1 expressionon the IRBC surface. PfEMP1 was still present in Maurer's clefts,and the transport and localization of several other Maurer'scleft proteins were unchanged. Maurer's clefts were alteredin appearance and were no longer found as close to the peripheryof the IRBC. Complementation of mutant parasites with sbp1 ledto the reappearance of PfEMP1 on the IRBC surface and the restorationof adhesion. Our results demonstrate that SBP1 is essentialfor the translocation of PfEMP1 onto the surface of IRBCs andis likely to play a pivotal role in the pathogenesis of P. falciparummalaria.

Abbreviations used in this paper: FRET, fluorescent resonanceenergy transfer; hdhfr, human dihydrofolate reductase; HRP,histidine-rich protein; HSP, heat shock protein; IFA, immunofluorescenceassay; IRBC, infected RBC; KAHRP, knob-associated HRP; KO, knockout;MAHRP, Maurer's cleft–associated HRP; PEXEL, Plasmodiumexport element; PfEMP, Plasmodium falciparum erythrocyte membraneprotein; REX, ring-stage exported protein; SBP1, skeleton-bindingprotein 1; VTS, vacuolar transport signal.

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