{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:30:18Z","timestamp":1780457418328,"version":"3.54.1"},"reference-count":74,"publisher":"Wiley","issue":"32","license":[{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171741"],"award-info":[{"award-number":["82171741"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170470"],"award-info":[{"award-number":["32170470"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371761"],"award-info":[{"award-number":["82371761"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010031","name":"Postdoctoral Research Foundation of China","doi-asserted-by":"publisher","award":["2021M701622"],"award-info":[{"award-number":["2021M701622"]}],"id":[{"id":"10.13039\/501100010031","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515010421"],"award-info":[{"award-number":["2023A1515010421"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Toxoplasma gondii<\/jats:italic> (<jats:italic>T. gondii<\/jats:italic>)\u2010associated polymorphic effector proteins are crucial in parasite development and regulating host anti\u2010<jats:italic>T. gondii<\/jats:italic> immune responses. However, the mechanism remains obscure. Here, it is shown that <jats:italic>Toxoplasma<\/jats:italic> effector dense granules 4 (GRA4) restricts host IFN\u2010I activation. Infection with \u0394<jats:italic>gra4<\/jats:italic> mutant <jats:italic>T. gondii<\/jats:italic> strain induces stronger IFN\u2010I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27\u2010catalyzed K48\u2010ubiquitination at Lys251\/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent \u0394<jats:italic>gra4<\/jats:italic> strain (ME49\u0394<jats:italic>ompdc<\/jats:italic>\/<jats:italic>gra4<\/jats:italic>) is constructed for tumor immunotherapy due to its ability to enhance IFN\u2010I production. Earlier vaccination with ME49\u0394<jats:italic>ompdc<\/jats:italic>\/<jats:italic>gra4<\/jats:italic> confers complete host resistance to the tumor compared with the classical ME49\u0394<jats:italic>ompdc<\/jats:italic> treatment. Notably, ME49\u0394<jats:italic>ompdc<\/jats:italic>\/<jats:italic>gra4<\/jats:italic> vaccination induces a specific CD64<jats:sup>+<\/jats:sup>MAR\u20101<jats:sup>+<\/jats:sup>CD11b<jats:sup>+<\/jats:sup> dendritic cell subset, thereby enhancing T cell anti\u2010tumor responses. Overall, these findings identify the negative role of <jats:italic>T. gondii<\/jats:italic> GRA4 in modulating host IFN\u2010I signaling and suggest that GRA4 can be a potential target for the development of <jats:italic>T. gondii<\/jats:italic> vaccines and tumor immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.202400952","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T14:55:45Z","timestamp":1718981745000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The <i>Toxoplasma<\/i> Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti\u2010<i>T. Gondii<\/i> Immunity and Tumor Immunotherapy"],"prefix":"10.1002","volume":"11","author":[{"given":"Zhiqiang","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"},{"name":"Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine Zhejiang University School of Medicine Zhejiang University  Hangzhou 310029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchao","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, School of Life Sciences Sun Yat\u2010sen University  Guangzhou 510275 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolin","family":"Fan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine Huazhong Agricultural University  Wuhan 430070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxin","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiansen","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"},{"name":"Department of Joint Surgery the Fifth Affiliated Hospital of Southern Medical University  Guangzhou 510900 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaji","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"},{"name":"Yue Bei People's Hospital Postdoctoral Innovation Practice Base Southern Medical University  Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huadan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"},{"name":"Guangdong Provincial Key Laboratory of Proteomics Southern Medical University  Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bang","family":"Shen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine Huazhong Agricultural University  Wuhan 430070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao\u2010Rong","family":"Lun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocontrol, School of Life Sciences Sun Yat\u2010sen University  Guangzhou 510275 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2491-9110","authenticated-orcid":false,"given":"Xiao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Southern Medical University Guangzhou 510515 China"},{"name":"Department of Clinical Laboratory Medicine, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences) Southern Medical University  Guangzhou 510000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00518-7"},{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2022.102226"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-019-0353-9"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2021.105312"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00005-17"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(99)00092-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/14760584.2023.2157818"},{"key":"e_1_2_9_6_1","volume":"13","author":"Hu Z.","year":"2022","journal-title":"mBio"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3787"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.940756"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.009172"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.05.013"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12893"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2018.06.003"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.27606"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2015.08.010"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20170035"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.259630"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM117.000117"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2019.1601702"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00833-9"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060815-014922"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-022-01088-2"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.108"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.041"},{"key":"e_1_2_9_22_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040528"},{"key":"e_1_2_9_22_3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040520"},{"key":"e_1_2_9_22_4","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.18.4976"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2013.07.001"},{"key":"e_1_2_9_23_2","first-page":"11a","volume":"9","author":"Zhu Y. C.","year":"2021","journal-title":"J. immunother. of cancer"},{"key":"e_1_2_9_23_3","doi-asserted-by":"publisher","DOI":"10.1186\/s13071-021-05032-6"},{"key":"e_1_2_9_23_4","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00508-21"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3845"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112043"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0210-z"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00741-5"},{"key":"e_1_2_9_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3200"},{"key":"e_1_2_9_27_3","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2009.00866.x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.005"},{"key":"e_1_2_9_29_1","first-page":"218","author":"Frickel E. M.","year":"2021","journal-title":"J. Exp. Med."},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003779"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02352-y"},{"key":"e_1_2_9_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2020.03.001"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.589604"},{"key":"e_1_2_9_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.902428"},{"key":"e_1_2_9_32_3","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3767"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100882"},{"key":"e_1_2_9_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2013.12.005"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00115-19"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/21.Supplement_1.S49"},{"key":"e_1_2_9_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2009.12.011"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2022.02.003"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00007.2017"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-021-07222-8"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028925"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3024.1994.tb00353.x"},{"key":"e_1_2_9_40_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.580425"},{"key":"e_1_2_9_40_3","first-page":"419","volume":"85","author":"Brown C. R.","year":"1995","journal-title":"Immunology"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020117-043952"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc4552"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.959300"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00990-6"},{"key":"e_1_2_9_44_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00939-6"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1004163"},{"key":"e_1_2_9_45_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101159"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.10.020"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02289-2"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01114-14"},{"key":"e_1_2_9_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6472-7_6"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01814"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.10.026"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg2339"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_9_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202400952","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T14:02:27Z","timestamp":1759759347000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202400952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,21]]},"references-count":74,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1002\/advs.202400952"],"URL":"https:\/\/doi.org\/10.1002\/advs.202400952","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,21]]},"assertion":[{"value":"2024-01-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2400952"}}