A conserved domain targets exported PHISTb family proteins to the periphery of Plasmodium infected erythrocytes

Graphical abstract

The extended PRESAN domain is a targeting domain used by multiple Plasmodium species to target PHISTb proteins to the cytoskeleton/plasma membrane of infected cells.

Highlights

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  Multiple P. falciparum PHISTb proteins localise to the erythrocyte periphery.

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  Solubility profiling indicates that these proteins associate with the red cell cytoskeleton.

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  The PRESAN domain and a preceding N-terminal sequence is a novel targeting domain.

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  A protein targeted to the red cell periphery is essential for parasite survival.

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  P. knowlesi and P. vivax homologous domains also confer similar localisation.

Abstract

During blood-stage infection, malaria parasites export numerous proteins to the host erythrocyte. The Poly-Helical Interspersed Sub-Telomeric (PHIST) proteins are an exported family that share a common ‘PRESAN’ domain, and include numerous members in Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi. In P. falciparum, PHIST proteins have been implicated in protein trafficking and intercellular communication. A number of PHIST proteins are essential for parasite survival. Here, we identify nine members of the PHISTb sub-class of PHIST proteins, including one protein known to be essential for parasite survival, that localise to the erythrocyte periphery. These proteins have solubility characteristics consistent with their association with the erythrocyte cytoskeleton. Together, an extended PRESAN domain, comprising the PRESAN domain and preceding sequence, form a novel targeting-domain that is sufficient to localise a protein to the erythrocyte periphery. We validate the role of this domain in RESA, thus identifying a cytoskeleton-binding domain in RESA that functions independently of its known spectrin-binding domain. Our data suggest that some PHISTb proteins may act as cross-linkers of the erythrocyte cytoskeleton. We also show for the first time that peripherally-localised PHISTb proteins are encoded in genomes of P. knowlesi and vivax indicating a conserved role for the extended PRESAN domain of these proteins in targeting to the erythrocyte periphery.