An aspartyl protease directs malaria effector proteins to the host cell.
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.
The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.
Justin A
JA
Boddey
Anthony N
AN
Hodder
Svenja
S
Günther
Paul R
PR
Gilson
Heather
H
Patsiouras
Eugene A
EA
Kapp
J Andrew
JA
Pearce
Tania F
TF
de Koning-Ward
Richard J
RJ
Simpson
Brendan S
BS
Crabb
Alan F
AF
Cowman
D020816:Amino Acid Motifs; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism* / Q000469:parasitology; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood* / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021382:Protein Sorting Signals; D021381:Protein Transport; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*
D000962:Antimalarials; D017320:HIV Protease Inhibitors; D021382:Protein Sorting Signals; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin