A repeat sequence domain of the ring-exported protein-1 ofPlasmodium falciparumcontrols export machinery architecture and virulence protein trafficking

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The malaria parasitePlasmodium falciparumdramatically remodels its host red blood cell to enhance its own survival, using a secretory membrane system that it establishes outside its own cell. Cisternal organelles, called Maurer's clefts, act as a staging point for the forward trafficking of virulence proteins to the red blood cell (RBC) membrane. The Ring-EXported Protein-1 (REX1) is a Maurer's cleft resident protein. We show that inducible knockdown of REX1 causes stacking of Maurer's cleft cisternae without disrupting the organization of the knob-associated histidine-rich protein at the RBC membrane. Genetic dissection of the REX1 sequence shows that loss of a repeat sequence domain results in the formation of giant Maurer's cleft stacks. The stacked Maurer's clefts are decorated with tether-like structures and retain the ability to dock onto the RBC membrane skeleton. The REX1 mutant parasites show deficient export of the major virulence protein, PfEMP1, to the red blood cell surface and markedly reduced binding to the endothelial cell receptor, CD36. REX1 is predicted to form a largely α-helical structure, with a repetitive charge pattern in the repeat sequence domain, providing potential insights into the role of REX1 in Maurer's cleft sculpting.

The malaria parasite Plasmodium falciparum generates protein trafficking organelles called Maurer's clefts in the cytoplasm of its host red blood cell. We show that the ring-exported protein-1 (REX1), a protein associated with these organelles, is responsible for Maurer's clefts sculpting and for efficient delivery of the major virulence protein to the red blood cell surface. Deletion of a repeat domain in REX1 leads to giant stacked Maurer's clefts.

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