MSY Tan
Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor
Tan, MSY; Koussis, K; Withers-Martinez, C; Howell, SA; Thomas, JA; Hackett, F; Knuepfer, E; Shen, M; Hall, MD; Snijders, AP; Blackman, MJ
Authors
K Koussis
C Withers-Martinez
SA Howell
JA Thomas
F Hackett
E Knuepfer
M Shen
MD Hall
AP Snijders
MJ Blackman
Abstract
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 beta-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 beta-spectrin cleavage and RBC rupture. Drug-like inhibitors of SERA6 autoprocessing similarly prevent beta-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.
Citation
Tan, M., Koussis, K., Withers-Martinez, C., Howell, S., Thomas, J., Hackett, F., …Blackman, M. (2021). Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor. EMBO Journal, 40(11), https://doi.org/10.15252/embj.2020107226
Journal Article Type | Article |
---|---|
Acceptance Date | May 1, 2021 |
Publication Date | 2021 |
Deposit Date | Dec 22, 2021 |
Publicly Available Date | Dec 22, 2021 |
Print ISSN | 0261-4189 |
Electronic ISSN | 1460-2075 |
Publisher | EMBO Press |
Peer Reviewed | Peer Reviewed |
Volume | 40 |
Issue | 11 |
DOI | https://doi.org/10.15252/embj.2020107226 |
Keywords | cofactor; egress; malaria; Plasmodium falciparum; protease |
Public URL | https://rvc-repository.worktribe.com/output/1553921 |
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
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