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Elife. 2017 Sep 12;6. pii: e27480. doi: 10.7554/eLife.27480.

A druggable secretory protein maturase of Toxoplasma essential for invasion and egress.

Author information

1
Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
2
Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland.
3
Chemical Biology of Antibiotics, Center for Infection and Immunity, Inserm U1019, CNRS UMR8204, Institut Pasteur de Lille, Lille, France.
4
Institute of Parasitology, University of Zurich, Zurich, Switzerland.

Abstract

Micronemes and rhoptries are specialized secretory organelles that deploy their contents at the apical tip of apicomplexan parasites in a regulated manner. The secretory proteins participate in motility, invasion, and egress and are subjected to proteolytic maturation prior to organellar storage and discharge. Here we establish that Toxoplasma gondii aspartyl protease 3 (ASP3) resides in the endosomal-like compartment and is crucially associated to rhoptry discharge during invasion and to host cell plasma membrane lysis during egress. A comparison of the N-terminome, by terminal amine isotopic labelling of substrates between wild type and ASP3 depleted parasites identified microneme and rhoptry proteins as repertoire of ASP3 substrates. The role of ASP3 as a maturase for previously described and newly identified secretory proteins is confirmed in vivo and in vitro. An antimalarial compound based on a hydroxyethylamine scaffold interrupts the lytic cycle of T. gondii at submicromolar concentration by targeting ASP3.

KEYWORDS:

Apicomplexa; Toxoplasma gondii; aspartyl protease; infectious disease; invasion and egress; microbiology; micronemes and rhoptries; peptidomimetic inhibitor

PMID:
28898199
PMCID:
PMC5595437
DOI:
10.7554/eLife.27480
[Indexed for MEDLINE]
Free PMC Article

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