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Global Identification of Multiple Substrates for Plasmodium falciparum SUB1, an Essential Malarial Processing Protease

Author:
Silmon de Monerri, Natalie C., Flynn, Helen R., Campos, Marta G., Hackett, Fiona, Koussis, Konstantinos, Withers-Martinez, Chrislaine, Skehel, J. Mark, Blackman, Michael J.
Source:
Infection and immunity 2011 v.79 no.3 pp. 1086-1097
ISSN:
0019-9567
Subject:
Plasmodium falciparum, antigens, bioinformatics, cell membranes, drugs, erythrocytes, humans, malaria, merozoites, parasites, pathogens, proteinases, proteolysis, proteome, proteomics, surface proteins, vacuoles
Abstract:
The protozoan pathogen responsible for the most severe form of human malaria, Plasmodium falciparum, replicates asexually in erythrocytes within a membrane-bound parasitophorous vacuole (PV). Following each round of intracellular growth, the PV membrane (PVM) and host cell membrane rupture to release infectious merozoites in a protease-dependent process called egress. Previous work has shown that, just prior to egress, an essential, subtilisin-like parasite protease called PfSUB1 is discharged into the PV lumen, where it directly cleaves a number of important merozoite surface and PV proteins. These include the essential merozoite surface protein complex MSP1/6/7 and members of a family of papain-like putative proteases called SERA (serine-rich antigen) that are implicated in egress. To determine whether PfSUB1 has additional, previously unrecognized substrates, we have performed a bioinformatic and proteomic analysis of the entire late asexual blood stage proteome of the parasite. Our results demonstrate that PfSUB1 is responsible for the proteolytic processing of a range of merozoite, PV, and PVM proteins, including the rhoptry protein RAP1 (rhoptry-associated protein 1) and the merozoite surface protein MSRP2 (MSP7-related protein-2). Our findings imply multiple roles for PfSUB1 in the parasite life cycle, further supporting the case for considering the protease as a potential new antimalarial drug target.
Agid:
290091