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

eLife

Adrian B Hehl¹  Luca Molino²  Ruben C Hartkoorn²  Pierre-Mehdi Hammoudi²  Sunil Kumar Dogga²  Budhaditya Mukherjee²  Damien Jacot²  Tobias Kockmann³  Dominique Soldati-Favre⁴ 

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

关键词: Apicomplexa;    Toxoplasma gondii;    aspartyl protease;    peptidomimetic inhibitor;    micronemes and rhoptries;    invasion and egress;   

DOI  :  10.7554/eLife.27480

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown