Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor.
Tan, Michele SY;
Koussis, Konstantinos;
Withers-Martinez, Chrislaine;
Howell, Steven A;
Thomas, James A;
Hackett, Fiona;
Knuepfer, Ellen;
Shen, Min;
Hall, Matthew D;
Snijders, Ambrosius P;
+1 more...Blackman, Michael J;
(2021)
Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor.
The EMBO journal, 40 (11).
e107226-.
ISSN 0261-4189
DOI: https://doi.org/10.15252/embj.2020107226
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Malaria parasite egress from host erythrocytes (RBCs) is regulated by discharge of a parasite serine protease called SUB1 into the parasitophorous vacuole (PV). There, SUB1 activates a PV-resident cysteine protease called SERA6, enabling host RBC rupture through SERA6-mediated degradation of the RBC cytoskeleton protein β-spectrin. Here, we show that the activation of Plasmodium falciparum SERA6 involves a second, autocatalytic step that is triggered by SUB1 cleavage. Unexpectedly, autoproteolytic maturation of SERA6 requires interaction in multimolecular complexes with a distinct PV-located protein cofactor, MSA180, that is itself a SUB1 substrate. Genetic ablation of MSA180 mimics SERA6 disruption, producing a fatal block in β-spectrin cleavage and RBC rupture. Drug-like inhibitors of SERA6 autoprocessing similarly prevent β-spectrin cleavage and egress in both P. falciparum and the emerging zoonotic pathogen P. knowlesi. Our results elucidate the egress pathway and identify SERA6 as a target for a new class of antimalarial drugs designed to prevent disease progression.