Proteolytic Activation of the Essential Parasitophorous Vacuole Cysteine Protease SERA6 Accompanies Malaria Parasite Egress from Its Host Erythrocyte
| Autor: | Katarina Milutinovic, Elizabeth M. A. Hirst, Chrislaine Withers-Martinez, Michael J. Blackman, Michael Shea, Catherine Suarez, Fiona Hackett, Andrea Ruecker |
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| Rok vydání: | 2012 |
| Předmět: |
Plasmodium
Erythrocytes medicine.medical_treatment Protozoan Proteins Vacuole Biochemistry Substrate Specificity Serine Cysteine Proteases Subtilisins Malaria Falciparum Microscopy Immunoelectron 0303 health sciences medicine.diagnostic_test biology 030302 biochemistry & molecular biology Egress Molecular Bases of Disease Cysteine protease Recombinant Proteins 3. Good health Cell biology Serine Protease Microbial Pathogenesis Proteases Proteolysis Blotting Western Molecular Sequence Data Plasmodium falciparum Host-Parasite Interactions 03 medical and health sciences medicine Amino Acid Sequence Molecular Biology 030304 developmental biology Serine protease Protease Binding Sites Sequence Homology Amino Acid SUB1 Cell Biology biology.organism_classification Malaria Enzyme Activation SERA Mutation Vacuoles biology.protein Cysteine Protease |
| Zdroj: | Journal of Biological Chemistry The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Background: Malaria parasite egress from host erythrocytes requires cysteine protease activity, but the identity of key parasite proteases is unknown. Results: SERA6 is an essential parasite cysteine protease that resides in the parasitophorous vacuole and is activated by SUB1, a parasite serine protease. Conclusion: SERA6 may play a role in egress. Significance: SERA6 is a potential new antimalarial drug target. The malaria parasite replicates within an intraerythrocytic parasitophorous vacuole (PV). The PV and host cell membranes eventually rupture, releasing merozoites in a process called egress. Certain inhibitors of serine and cysteine proteases block egress, indicating a crucial role for proteases. The Plasmodium falciparum genome encodes nine serine-repeat antigens (SERAs), each of which contains a central domain homologous to the papain-like (clan CA, family C1) protease family. SERA5 and SERA6 are indispensable in blood-stage parasites, but the function of neither is known. Here we show that SERA6 localizes to the PV where it is precisely cleaved just prior to egress by an essential serine protease called PfSUB1. Mutations that replace the predicted catalytic Cys of SERA6, or that block SERA6 processing by PfSUB1, could not be stably introduced into the parasite genomic sera6 locus, indicating that SERA6 is an essential enzyme and that processing is important for its function. We demonstrate that cleavage of SERA6 by PfSUB1 converts it to an active cysteine protease. Our observations reveal a proteolytic activation step in the malarial PV that may be required for release of the parasite from its host erythrocyte. |
| Databáze: | OpenAIRE |
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