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The subset of GRAs residing in the parasitophorous vacuole (PV) or exported into the host cell, undergo proteolytic cleavage in the Golgi upon the action of the aspartyl protease 5 (ASP5). In tachyzoites, ASP5 substrates play central roles in the morphology of the PV and the export of effectors across the translocon complex MYR1\/2\/3. Here, we used N\u2010terminal amine isotopic labeling of substrates to identify novel ASP5 cleavage products by comparing the N\u2010terminome of wild\u2010type and \u0394<jats:italic>asp5<\/jats:italic> lines in tachyzoites and bradyzoites. Validated substrates reside within the PV or PVM in an ASP5\u2010dependent manner. Remarkably, \u0394<jats:italic>asp5<\/jats:italic> bradyzoites are impaired in the formation of the cyst wall in vitro and exhibit a considerably reduced cyst burden in chronically infected animals. More specifically two\u2010photon serial tomography of infected mouse brains revealed a comparatively reduced number and size of the cysts throughout the establishment of persistence in the absence of ASP5.<\/jats:p>","DOI":"10.1111\/mmi.14987","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T11:32:45Z","timestamp":1665401565000},"page":"601-622","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Importance of aspartyl protease 5 in the establishment of the intracellular niche during acute and chronic infection of <i>Toxoplasma gondii<\/i>"],"prefix":"10.1111","volume":"118","author":[{"given":"Sunil Kumar","family":"Dogga","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Medicine University of Geneva  Geneva 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