Processing of Plasmodium falciparum Merozoite Surface Protein MSP1 Activates a Spectrin-Binding Function Enabling Parasite Egress from RBCs

• Published in: Cell host & microbe Vol. 18; no. 4; pp. 433 - 444
• Main Authors: Das, Sujaan, Hertrich, Nadine, Perrin, Abigail J., Withers-Martinez, Chrislaine, Collins, Christine R., Jones, Matthew L., Watermeyer, Jean M., Fobes, Elmar T., Martin, Stephen R., Saibil, Helen R., Wright, Gavin J., Treeck, Moritz, Epp, Christian, Blackman, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.10.2015; Cell Press
• Subjects: Erythrocytes - parasitology; Host-Pathogen Interactions; Humans; Merozoite Surface Protein 1 - chemistry; Merozoite Surface Protein 1 - metabolism; Merozoites - enzymology; Merozoites - physiology; Models, Biological; Plasmodium falciparum; Plasmodium falciparum - enzymology; Plasmodium falciparum - physiology; Protein Binding; Protein Conformation; Protein Processing, Post-Translational; Proteolysis; Protozoan Proteins - metabolism; Spectrin - metabolism; Subtilisins - metabolism
• DOI: 10.1016/j.chom.2015.09.007
• ISSN: 1931-3128; 1934-6069

The malaria parasite Plasmodium falciparum replicates within erythrocytes, producing progeny merozoites that are released from infected cells via a poorly understood process called egress. The most abundant merozoite surface protein, MSP1, is synthesized as a large precursor that undergoes proteolytic maturation by the parasite protease SUB1 just prior to egress. The function of MSP1 and its processing are unknown. Here we show that SUB1-mediated processing of MSP1 is important for parasite viability. Processing modifies the secondary structure of MSP1 and activates its capacity to bind spectrin, a molecular scaffold protein that is the major component of the host erythrocyte cytoskeleton. Parasites expressing an inefficiently processed MSP1 mutant show delayed egress, and merozoites lacking surface-bound MSP1 display a severe egress defect. Our results indicate that interactions between SUB1-processed merozoite surface MSP1 and the spectrin network of the erythrocyte cytoskeleton facilitate host erythrocyte rupture to enable parasite egress. [Display omitted] •Merozoite surface protein MSP1 processing is important for P. falciparum viability•Proteolytic processing activates MSP1’s heparin and spectrin-binding functions•The rate of MSP1 processing governs the kinetics of parasite egress•Loss of parasite surface MSP1 results in a severe egress defect Egress from infected RBCs is a critical, but poorly understood, step in the malaria parasite’s lifecycle. Das et al. report that just prior to egress, proteolytic processing of parasite surface protein MSP1 activates a spectrin binding function, allowing the intracellular parasite to interact with the RBC cytoskeleton and enabling egress.