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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2132-2139.
Prepublished online as a Blood First Edition Paper on May 25, 2007; DOI 10.1182/blood-2007-04-083873.
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Submitted April 5, 2007
Accepted May 22, 2007
Cytoplasmic remodeling of erythrocyte raft lipids during infection by the human malaria parasite Plasmodium falciparum
Sean C Murphy, Sebastian Fernandez-Pol, Paul H Chung, S N Prasanna Murthy, Stephen B Milne, Marcela Salomao, H Alex Brown, Jon W Lomasney, Narla Mohandas, and Kasturi Haldar*
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
New York Blood Center, New York, NY, United States
Department of Molecular Pharmacology & Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
* Corresponding author; email: k-haldar{at}northwestern.edu.
Studies of detergent resistant membrane (DRM) rafts in mature erythrocytes have facilitated identification of proteins that regulate formation of endovacuolar structures such as the parasitophorous vacuolar membrane (PVM) induced by the malaria parasite Plasmodium falciparum. However, analyses of raft lipids have remained elusive because detergents interfere with lipid detection. Here, we use primaquine to perturb the erythrocyte membrane and induce detergent-free buoyant vesicles, which are enriched in cholesterol and major raft proteins flotillin and stomatin and contain low levels of cytoskeleton, all characteristics of raft microdomains. Lipid mass spectrometry revealed that phosphatidylethanolamine and phosphatidylglycerol are depleted in endovesicles while phosphoinositides are highly enriched, suggesting raft-based endovesiculation can be achieved by simple (non-receptor-mediated) mechanical perturbation of the erythrocyte plasma membrane and results in sorting of inner leaflet phospholipids. Live-cell imaging of lipid-specific protein probes showed that phosphatidylinositol (4,5) bisphosphate (PIP2) is highly concentrated in primaquine-induced vesicles, confirming that it is an erythrocyte raft lipid. However, the malarial PVM lacks PIP2, although another raft lipid, phosphatidylserine, is readily detected. Thus, different remodeling/sorting of cytoplasmic raft phospholipids may occur in distinct endovacuoles. Importantly, erythrocyte raft lipids recruited to the invasion junction by mechanical stimulation may be remodeled by the malaria parasite to establish blood-stage infection.
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