Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte

Abstract

During their intraerythrocytic development, malaria parasites export hundreds of proteins to remodel their host cell. Nutrient acquisition, cytoadherence and antigenic variation are among the key virulence functions effected by this erythrocyte takeover. Proteins destined for export are synthesized in the endoplasmic reticulum (ER) and cleaved at a conserved (PEXEL) motif, which allows translocation into the host cell via an ATP-driven translocon called the PTEX complex. We report that plasmepsin V, an ER aspartic protease with distant homology to the mammalian processing enzyme BACE, recognizes the PEXEL motif and cleaves it at the correct site. This enzyme is essential for parasite viability and ER residence is essential for its function. We propose that plasmepsin V is the PEXEL protease and is an attractive enzyme for antimalarial drug development.

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

“…Some have emerged from studies focusing on other key biological events such as erythrocyte egress/invasion and merozoite surface antigen maturation such as the subtilisin-like proteases -1 and -2 and the cystein proteases DPAP3, SERA-5 and SERA-6 (Blackman, 2008). Other proteases for which essential roles during the parasite asexual development have been demonstrated include Plasmepsin V, involved in maturation of proteins exported to the infected-red blood cell (Boddey et al, 2010, Russo et al, 2010. During these investigations, some proteases were found dispensable for the parasite asexual development in erythrocyte but important in other stages such as gametogenesis or the development of insect stages (Sologub et al, 2011).…”

PEXEL-independent trafficking of Plasmodium falciparum SURFIN4.2 to the parasite-infected red blood cell and Maurer's clefts

“…The mechanisms that enable such trafficking are incompletely understood; however, many P. falciparum proteins destined for export into the iRBC contain both an N-terminal hydrophobic signal sequence and a short conserved pentameric host cell-targeting motif (RxLxE/Q/D) termed the Plasmodium export element (PEXEL) or the vacuolar transport signal (VTS) [8,9]. The N-terminal signal sequence is required for the proteins to enter the constitutive secretory pathway via the endoplasmic reticulum (ER) [10,11], where the PEXEL/VTS motif is cleaved by plasmepsin V, an ER residing aspartic protease [12,13], and the newly formed N-terminus (xE/Q/D) allows translocation into the iRBC cytosol by a PVM residing translocon called the "Plasmodium translocon of exported proteins" (PTEX) complex [14]. Our understanding of the mechanisms behind the transport of proteins within the iRBC remains vague, but some tentative explanations have been raised; transport may be mediated through vesicles, through complex membrane networks, non-lipid enclosed protein aggregates, or lipid enclosed structures such as Maurer's clefts [4,15].…”

Toxoplasma gondii aspartic protease 1 is not essential in tachyzoites

“…Most recently, PfPMV has been localized to the endoplasmic reticulum (ER) and was demonstrated to be essential for parasite viability and hence represents a new target for therapeutic intervention against malaria. PfPMV cleaves exported proteins at a conserved PEXEL motif allowing translocation of several hundred proteins to the host cell cytoplasm via the ATP driven translocator PTEX to remodel the host cell in order to survive and evade the host response (Boddey et al, 2010;Russo et al, 2010).…”