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    A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells

    Thomas, J.A. and Tan, M.S.Y. and Bisson, C. and Borg, A. and Umrekar, T.R. and Hackett, F. and Hale, V.L. and Vizcay-Barrena, G. and Fleck, R.A. and Snijders, A. and Saibil, Helen R. and Blackman, M.J. (2018) A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells. Nature Microbiology 3 , pp. 447-455. ISSN 2058-5276.

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    Malaria parasites replicate within a parasitophorous vacuole in red blood cells (RBCs). Progeny merozoites egress upon rupture of first the parasitophorous vacuole membrane (PVM), then poration and rupture of the RBC membrane (RBCM). Egress is protease-dependent1, but none of the effector molecules that mediate membrane rupture have been identified and it is unknown how sequential rupture of the two membranes is controlled. Minutes before egress, the parasite serine protease SUB1 is discharged into the parasitophorous vacuole2,3,4,5,6 where it cleaves multiple substrates2,5,7,8,9 including SERA6, a putative cysteine protease10,11,12. Here, we show that Plasmodium falciparum parasites lacking SUB1 undergo none of the morphological transformations that precede egress and fail to rupture the PVM. In contrast, PVM rupture and RBCM poration occur normally in SERA6-null parasites but RBCM rupture does not occur. Complementation studies show that SERA6 is an enzyme that requires processing by SUB1 to function. RBCM rupture is associated with SERA6-dependent proteolytic cleavage within the actin-binding domain of the major RBC cytoskeletal protein β-spectrin. We conclude that SUB1 and SERA6 play distinct, essential roles in a coordinated proteolytic cascade that enables sequential rupture of the two bounding membranes and culminates in RBCM disruption through rapid, precise, SERA6-mediated disassembly of the RBC cytoskeleton.


    Item Type: Article
    Additional Information: Publisher correction available at
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Administrator
    Date Deposited: 20 Feb 2018 10:24
    Last Modified: 02 Aug 2023 17:39


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