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In this study, we performed a genome-wide CRISPR screen and identified the dense granule proteins GRA35, GRA42, and GRA43 as the\n              <jats:italic>Toxoplasma<\/jats:italic>\n              effectors mediating cell death in Lewis rat macrophages. GRA35 localizes on the parasitophorous vacuole membrane, where it interacts with the host E3 ubiquitin ligase ITCH. Inhibition of proteasome activity or ITCH knockout prevented pyroptosis in\n              <jats:italic>Toxoplasma<\/jats:italic>\n              -infected Lewis rat macrophages, consistent with the \u201cNLRP1 functional degradation model.\u201d However, there was no evidence that ITCH directly ubiquitinates or interacts with rat NLRP1. We also found that GRA35-ITCH interaction affected\n              <jats:italic>Toxoplasma<\/jats:italic>\n              fitness in IFN\u03b3-activated human fibroblasts, likely due to ITCH\u2019s role in recruiting ubiquitin and the parasite-restriction factor RNF213 to the parasitophorous vacuole membrane. These findings identify a new role of host E3 ubiquitin ligase ITCH in mediating effector-triggered immunity, a critical concept that involves recognizing intracellular pathogens and initiating host innate immune responses.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Effector-triggered immunity represents an innate immune defense mechanism that plays a crucial role in sensing and controlling intracellular pathogen infection. The NLRP1 inflammasome in the Lewis rats can detect\n                <jats:italic>Toxoplasma<\/jats:italic>\n                infection, which triggers proptosis in infected macrophages and eliminates the parasite\u2019s replication niche. The work reported here revealed that host E3 ubiquitin ligase ITCH is able to recognize and interact with\n                <jats:italic>Toxoplasma<\/jats:italic>\n                effector protein GRA35 localized on the parasite-host interface, leading to NLRP1 inflammasome activation in Lewis rat macrophages. Furthermore, ITCH-GRA35 interaction contributes to the restriction of\n                <jats:italic>Toxoplasma<\/jats:italic>\n                in human fibroblasts stimulated by IFN\u03b3. Thus, this research provides valuable insights into understanding pathogen recognition and restriction mediated by host E3 ubiquitin ligase.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.03302-23","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T14:17:55Z","timestamp":1708438675000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Host E3 ubiquitin ligase ITCH mediates\n            <i>Toxoplasma gondii<\/i>\n            effector GRA35-triggered NLRP1 inflammasome activation and cell-autonomous immunity"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9451-0041","authenticated-orcid":true,"given":"Yifan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology &amp; Immunology, School of Veterinary Medicine, University of California, Davis, California, USA"},{"name":"Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Robert","family":"Hollingsworth","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamba Omar","family":"Sangar\u00e9","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology &amp; Immunology, School of Veterinary Medicine, University of California, Davis, California, USA"},{"name":"Department of Biology, Texas A&amp;M University, College Station, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana C.","family":"Paredes-Santos","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology &amp; Immunology, School of Veterinary Medicine, University of California, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruthi","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology &amp; Immunology, School of Veterinary Medicine, University of California, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bennett H.","family":"Penn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, UC Davis Health, Sacramento, California, USA"},{"name":"Department of Medical Microbiology and Immunology, University of California, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0289-7109","authenticated-orcid":true,"given":"Jeroen P. 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