Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor. (1st May 2021)

• Record Type: Journal Article
• Authors: Tan, Michele S Y; Koussis, Konstantinos; Withers‐Martinez, Chrislaine; Howell, Steven A; Thomas, James A; Hackett, Fiona; Knuepfer, Ellen; Shen, Min; Hall, Matthew D; Snijders, Ambrosius P; Blackman, Michael J
• Is Part Of: EMBO journal. Volume 40:Number 11(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-01
• Subjects: cofactor -- egress -- malaria -- Plasmodium falciparum -- protease; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020107226
• Languages: English
• ISSNs: 0261-4189

Abstract

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 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. SYNOPSIS: Escape (egress) of the malaria parasite Plasmodium falciparum from host red blood cells requires proteolytic cleavage of the parasite cysteine protease SERA6 by a serine protease called SUB1, but subsequent requirements for SERA6 activation are unknown. Here it is shown that SERA6 maturation occurs through further autocatalytic cleavage that involves interaction with an essential partner protein. Activation of the parasitophorous vacuole (PV)‐located egress protease SERA6 occurs via an autocatalytic step that is triggered by SUB1‐mediated cleavage. Autocatalytic maturation of SERA6 needs a PV‐located protein cofactor, MSA180, which is also a SUB1 substrate. SERA6 maturation is blocked by drug‐like compounds that inhibit egress, identifying SERA6 as a potential target for a new class of antimalarial drugs. Abstract : Escape of the malaria parasite Plasmodium falciparum from host red blood cells requires maturation of the parasite cysteine protease SERA6 via an interaction with the parasitophorous vacuole protein MSA180.