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We previously identified TRIM21 as an IFN\u03b3-driven E3 ubiquitin ligase mediating the deposition of ubiquitin around pathogen inclusions. Here, we show that TRIM21 knockout mice were highly susceptible to<jats:italic>Toxoplasma<\/jats:italic>infection, exhibiting decreased levels of serum inflammatory cytokines and higher parasite burden in the peritoneum and brain. We demonstrate that IFN\u03b3 drives recruitment of TRIM21 to GBP1-positive<jats:italic>Toxoplasma<\/jats:italic>vacuoles, leading to Lys63-linked ubiquitination of the vacuole and restriction of parasite early replication without interfering with vacuolar disruption. As seen<jats:italic>in vivo<\/jats:italic>, TRIM21 impacted the secretion of inflammatory cytokines. This study identifies TRIM21 as a previously unknown modulator of<jats:italic>Toxoplasma gondii<\/jats:italic>resistance<jats:italic>in vivo<\/jats:italic>thereby extending host innate immune recognition of eukaryotic pathogens to include E3 ubiquitin ligases.<\/jats:p>","DOI":"10.1038\/s41598-017-05487-7","type":"journal-article","created":{"date-parts":[[2017,7,6]],"date-time":"2017-07-06T10:09:20Z","timestamp":1499335760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["TRIM21 is critical for survival of Toxoplasma gondii infection and localises to GBP-positive parasite vacuoles"],"prefix":"10.1038","volume":"7","author":[{"given":"Cl\u00e9mence","family":"Foltz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Napolitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabia","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Clough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Hirst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-3442","authenticated-orcid":false,"given":"Eva-Maria","family":"Frickel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,12]]},"reference":[{"key":"5487_CR1","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1016\/S0140-6736(04)16412-X","volume":"363","author":"JG Montoya","year":"2004","unstructured":"Montoya, J. 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