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Published 25 September 2006. doi:10.1083/jcb.200604136
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 7, 1023-1033
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Article

 Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite

Rebecca A. O'Donnell1, Fiona Hackett1, Steven A. Howell2, Moritz Treeck3, Nicole Struck3, Zita Krnajski3, Chrislaine Withers-Martinez1, Tim W. Gilberger3, and Michael J. Blackman1

1 Division of Parasitology and 2 Protein Structure, National Institute for Medical Research, Mill Hill, London NW7 1AA, England, UK
3 Research Group Malaria II, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany

Correspondence to Michael J. Blackman: mblackm{at}nimr.mrc.ac.uk; or Tim W. Gilberger: gilberger{at}bni.uni-hamburg.de

Apicomplexan pathogens are obligate intracellular parasites. To enter cells, they must bind with high affinity to host cell receptors and then uncouple these interactions to complete invasion. Merozoites of Plasmodium falciparum, the parasite responsible for the most dangerous form of malaria, invade erythrocytes using a family of adhesins called Duffy binding ligand-erythrocyte binding proteins (DBL-EBPs). The best-characterized P. falciparum DBL-EBP is erythrocyte binding antigen 175 (EBA-175), which binds erythrocyte surface glycophorin A. We report that EBA-175 is shed from the merozoite at around the point of invasion. Shedding occurs by proteolytic cleavage within the transmembrane domain (TMD) at a site that is conserved across the DBL-EBP family. We show that EBA-175 is cleaved by PfROM4, a rhomboid protease that localizes to the merozoite plasma membrane, but not by other rhomboids tested. Mutations within the EBA-175 TMD that abolish cleavage by PfROM4 prevent parasite growth. Our results identify a crucial role for intramembrane proteolysis in the life cycle of this pathogen.

R.A. O'Donnell and F. Hackett contributed equally to this work.

R.A. O'Donnell's current address is Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.

Abbreviations used in this paper: AMA1, apical membrane antigen 1; DBL-EBP, Duffy binding ligand-erythrocyte binding protein; EBA-175, erythrocyte binding antigen 175; gDNA, genomic DNA; IFA, immunofluorescence assay; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; MPP1, microneme processing protease 1; MSP1, merozoite surface protein 1; TMD, transmembrane domain.


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