| Summary: | Adherence of <em>Plasmodium falciparum</em> infected erythrocytes to host endothelium is conferred through the parasite-derived virulence factor PfEMP1, the major contributor to malaria severity. PfEMP1 located at knob structures on the erythrocyte surface is anchored to the cytoskeleton, and the <em>Plasmodium</em> Helical Interspersed Sub-Telomeric (PHIST) gene family plays a role in many host cell modification including binding the intracellular domain of PfEMP1. Here, we show that conditional reduction of the PHIST protein PFE1605w strongly reduces adhesion of infected erythrocytes to the endothelial receptor CD36. Adhesion to other endothelial receptors was less affected or even unaltered by PFE1605w depletion, suggesting that PHIST proteins might be optimised for subsets of PfEMP1 variants. PFE1605w does not play a role for PfEMP1 transport, but directly interacts with both the intracellular segment of PfEMP1 and with cytoskeletal components. This is the first report of a PHIST protein interacting with key molecules of the cytoadherence complex and the host cytoskeleton and this functional role seems to play an essential role in the pathology of <em>P. falciparum</em>.
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