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J. Biol. Chem., Vol. 278, Issue 48, 48413-48421, November 28, 2003

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Identification of a Stomatin Orthologue in Vacuoles Induced in Human Erythrocytes by Malaria Parasites

A ROLE FOR MICROBIAL RAFT PROTEINS IN APICOMPLEXAN VACUOLE BIOGENESIS^*

N. Luisa Hiller, Thomas Akompong, Jon S. Morrow, Anthony A. Holder¶, and Kasturi Haldar||

From the Departments of Pathology and Microbiology-Immunology, Northwestern University, Chicago, Illinois 60611, the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, and the ^¶Division of Parasitology, National Institute for Medical Research, London NW 7 1AA, United Kingdom

When the human malaria parasite Plasmodium falciparum infects erythrocytes, proteins associated with host-derived detergent-resistant membrane (DRM) rafts are selectively recruited into the newly formed vacuole, but parasite proteins that contribute to raft-based vacuole development are unknown. In mammalian cells, DRM-associated integral membrane proteins such as caveolin-1 and flotillin-1 that form oligomers have been linked to the formation of DRM-based invaginations called caveolae. Here we show that the P. falciparum genome does not encode caveolins or flotillins but does contain an orthologue of human band 7 stomatin, a protein known to oligomerize, associate with non-caveolar DRMs and is distantly related to flotillins. Stomatins are members of a large protein family conserved in evolution and P. falciparum (Pf) stomatin appears to be a prokaryotic-like molecule. Evidence is presented that it associates with DRMs and may oligomerize, suggesting that these features are conserved in the stomatin family. Further, Pfstomatin is an integral membrane protein concentrated at the apical end of extracellular parasites, where it co-localizes with invasion-associated rhoptry organelles. A resident rhoptry protein, RhopH2 also resides in DRMs. This provides the first evidence that rhoptries of an apicomplexan parasite contain DRM rafts. Further, when the parasite invades erythrocytes, rhoptry Pfstomatin and RhopH2 are inserted into the newly formed vacuole. Thus, like caveolin-1 and flotillin-1, a stomatin may also associate with non-clathrin coated, DRM-enriched vacuoles. We propose a new model of invasion and vacuole formation involving DRM-based interactions of both host and parasite molecules.

Received for publication, July 7, 2003 , and in revised form, September 10, 2003.

^* This work was supported in part by Grant 0215246Z from the American Heart Association (to N. L. H.) and by Grant AI39071 (to K. H.) and Grant HL28560 (to J. S. M.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pathology and Microbiology-Immunology, Northwestern University, Chicago, IL 60611. Tel.: 312-503-0224; Fax: 312-503-8240; E-mail: k-haldar{at}northwestern.edu.

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