An aspartyl protease directs malaria effector proteins to the host cell

Abstract

Plasmodium falciparum causes the virulent form of malaria and disease manifestations are linked to growth inside infected erythrocytes. In order to survive and evade host responses the parasite remodels the erythrocyte by exporting several hundred effector proteins beyond the surrounding parasitophorous vacuole membrane. A feature of exported proteins is a pentameric motif (RxLxE/Q/D) that is a substrate for an unknown protease. Here, we show the protein responsible for cleavage of this motif is Plasmepsin V, an aspartic acid protease located in the endoplasmic reticulum. Plasmepsin V cleavage reveals the export signal (xE/Q/D) at the N-terminus of cargo proteins. Expression of an identical mature protein with xQ at the N-terminus generated by signal peptidase was not exported demonstrating Plasmepsin V activity is essential and linked with other key export events. Identification of the protease responsible for export into erythrocytes provides a novel target for therapeutic intervention against this devastating disease.

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).…”