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

doi:10.15252/embj.2020107226

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

MSY Tan

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
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