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

Author:

Silmon de Monerri Natalie C.1,Flynn Helen R.2,Campos Marta G.1,Hackett Fiona1,Koussis Konstantinos1,Withers-Martinez Chrislaine1,Skehel J. Mark2,Blackman Michael J.1

Affiliation:

1. Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

2. Protein Analysis and Proteomics Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, United Kingdom

Abstract

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.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Immunology,Microbiology,Parasitology

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