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


O'Donnell, RA; Hackett, F; Howell, SA; Treeck, M; Struck, N; Krnajski, Z; Withers-Martinez, C; Gilberger, TW; Blackman, MJ; (2006) Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite. The Journal of cell biology, 174 (7). pp. 1023-33. ISSN 0021-9525 DOI: https://doi.org/10.1083/jcb.200604136

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Abstract

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.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
PubMed ID: 17000879
Web of Science ID: 240946400012
URI: http://researchonline.lshtm.ac.uk/id/eprint/1544242

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