Fundamental Roles of the Golgi-Associated Toxoplasma Aspartyl Protease, ASP5, at the Host-Parasite Interface

Article Article scientifique Article Fundamental Roles of the Golgi-Associated Toxoplasma Aspartyl Protease, ASP5, at the Host-Parasite Interface eng 2015 author Hammoudi Pierre-Mehdi 811456 author Jacot Damien 707423 author Mueller Christina 713335 author Di Cristina Manlio author Dogga Sunil Kumar 816906 author Marq Jean-Baptiste 27225 author Romano Julia author Tosetti Nicolo 828676 author Dubrot Armendariz Juan 744966 author Emre Yalin 707967 author Lunghi Matteo author Coppens Isabelle author Yamamoto Masahiro author Sojka Daniel 788884 author Pino Paco 629465 author Soldati-Favre Dominique 0000-0003-4156-2109 135114 e1005211 10.1371/journal.ppat.1005211 26473595 1553-7366 Toxoplasma gondii possesses sets of dense granule proteins (GRAs) that either assemble at, or cross the parasitophorous vacuole membrane (PVM) and exhibit motifs resembling the HT/PEXEL previously identified in a repertoire of exported Plasmodium proteins. Within Plasmodium spp., cleavage of the HT/PEXEL motif by the endoplasmic reticulum-resident protease Plasmepsin V precedes trafficking to and export across the PVM of proteins involved in pathogenicity and host cell remodelling. Here, we have functionally characterized the T. gondii aspartyl protease 5 (ASP5), a Golgi-resident protease that is phylogenetically related to Plasmepsin V. We show that deletion of ASP5 causes a significant loss in parasite fitness in vitro and an altered virulence in vivo. Furthermore, we reveal that ASP5 is necessary for the cleavage of GRA16, GRA19 and GRA20 at the PEXEL-like motif. In the absence of ASP5, the intravacuolar nanotubular network disappears and several GRAs fail to localize to the PVM, while GRA16 and GRA24, both known to be targeted to the host cell nucleus, are retained within the vacuolar space. Additionally, hypermigration of dendritic cells and bradyzoite cyst wall formation are impaired, critically impacting on parasite dissemination and persistence. Overall, the absence of ASP5 dramatically compromises the parasite's ability to modulate host signalling pathways and immune responses. Dewey 616 Swiss National Science Foundation FN3100A0-116722 CH 54 Département de microbiologie et médecine moléculaire 21B false 443 Biologie d'un parasite intracellulaire obligatoire 773 PLOS pathogens 11 10 f1ba66d1-fe57-4274-8def-0d86358ae7b9 Article (Accepted version) Public journal.ppat.1005211.pdf 14814750 application/pdf openAccess Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire

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Fundamental Roles of the Golgi-Associated Toxoplasma Aspartyl Protease, ASP5, at the Host-Parasite Interface	PLOS pathogens			2015	731	363

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Sojka, Daniel