An aspartyl protease directs malaria effector proteins to the host cell

• Published in: Nature (London) Vol. 463; no. 7281; pp. 627 - 631
• Main Authors: Hodder, Anthony N, Simpson, Richard J, Crabb, Brendan S, Patsiouras, Heather, Boddey, Justin A, Cowman, Alan F, Pearce, J. Andrew, Günther, Svenja, Gilson, Paul R, de Koning-Ward, Tania F, Kapp, Eugene A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2010; Nature Publishing Group
• Subjects: 631/154/555; 631/250/255/1629; 631/45/607/468; 631/80/2023/2022; Amino Acid Motifs; Amino acids; Animals; Antimalarials - pharmacology; Aspartate; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - isolation & purification; Aspartic Acid Endopeptidases - metabolism; Biological and medical sciences; Cleavage; E coli; Effectors; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - metabolism; Erythrocytes; Erythrocytes - cytology; Erythrocytes - metabolism; Erythrocytes - parasitology; Exports; HIV Protease Inhibitors - pharmacology; Human protozoal diseases; Humanities and Social Sciences; Humans; Infectious diseases; International trade; Malaria; Malaria, Falciparum - blood; Malaria, Falciparum - metabolism; Malaria, Falciparum - parasitology; Malaria, Falciparum - pathology; Mass spectrometry; Medical sciences; multidisciplinary; Parasites; Parasitic diseases; Plasmodium falciparum; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Plasmodium falciparum - metabolism; Protease; Proteases; Protein Processing, Post-Translational - drug effects; Protein Sorting Signals; Protein Transport; Proteins; Protozoal diseases; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Questions and answers; Science; Science (multidisciplinary); Vector-borne diseases; Infection; Protozoal disease; Malaria; Host; Parasitosis; Effector; Protein
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08728

Plasmodium falciparum causes the virulent form of malaria and disease manifestations are linked to growth inside infected erythrocytes. 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 that the protein responsible for cleavage of this motif is plasmepsin V (PMV), an aspartic acid protease located in the endoplasmic reticulum. PMV cleavage reveals the export signal (xE/Q/D) at the amino terminus of cargo proteins. Expression of an identical mature protein with xQ at the N terminus generated by signal peptidase was not exported, demonstrating that PMV 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. Protease antimalarial target A key part of the life cycle of the malaria parasite — and the one that makes transmission via the mosquito to other hosts possible — involves a period of growth inside host red blood cells. During this phase the Plasmodium cells export several hundred proteins into the host blood cell, which they remodel as an environment suitable for parasite multiplication. Proteins destined for export contain a conserved motif called PEXEL, and when this is cleaved in the endoplasmic reticulum the protein can translocate into the host cell. Two independent studies now reveal the identity of the enzyme that cleaves the PEXEL motif as the aspartyl protease plasmepsin V. This finding immediately suggests that plasmepsin V is a potential drug target for antimalarial agents. To survive and evade host responses, malaria parasites export several hundred proteins into the host cell on infection. A feature of these proteins is a conserved, pentameric motif that is cleaved by an unknown protease before export. This is one of two independent studies revealing the identity of the protease as plasmepsin V, an aspartic acid protease located in the endoplasmic reticulum. This enzyme is essential for parasite viability and is an attractive candidate for drug development.