{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:56:03Z","timestamp":1790607363486,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T00:00:00Z","timestamp":1689379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010035","name":"Outstanding Youth Foundation of Jiangsu Province of China","doi-asserted-by":"publisher","award":["BK20190046"],"award-info":[{"award-number":["BK20190046"]}],"id":[{"id":"10.13039\/501100010035","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010035","name":"Outstanding Youth Foundation of Jiangsu Province of China","doi-asserted-by":"publisher","award":["2021M702760"],"award-info":[{"award-number":["2021M702760"]}],"id":[{"id":"10.13039\/501100010035","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["BK20190046"],"award-info":[{"award-number":["BK20190046"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M702760"],"award-info":[{"award-number":["2021M702760"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions (Veterinary Medicine)","award":["BK20190046"],"award-info":[{"award-number":["BK20190046"]}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions (Veterinary Medicine)","award":["2021M702760"],"award-info":[{"award-number":["2021M702760"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>cGAS-STING signaling is a major pathway in inducing type \u2160 IFN, which plays a crucial role in the defense against T. gondii infection. In contrast, T. gondii develops multiple strategies to counteract the host defense, causing serious diseases in a wide range of hosts. Here, we demonstrate that T. gondii rhoptry protein 16 (ROP16) dampens type I interferon signaling via the inhibition of the cGAS (cyclic GMP-AMP synthase) pathway through the polyubiquitination of STING. Mechanistically, ROP16 interacts with STING through the SignalP domain and inhibits the K63-linked ubiquitination of STING in an NLS (nuclear localization signal)-domain-dependent manner. Consequently, knocking out the ROP16 in PRU tachyzoites promotes the STING-mediated production of type I IFNs and limits the replication of T. gondii. Together, these findings describe a distinct pathway where T. gondii exploits the ubiquitination of STING to evade host anti-parasite immunity, revealing new insights into the interaction between the host and parasites.<\/jats:p>","DOI":"10.3390\/cells12141862","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:41:05Z","timestamp":1689554465000},"page":"1862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["ROP16 of Toxoplasma gondii Inhibits Innate Immunity by Triggering cGAS-STING Pathway Inactivity through the Polyubiquitination of STING"],"prefix":"10.3390","volume":"12","author":[{"given":"Qi-Wang","family":"Jin","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Pan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Min","family":"Fan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1452-1299","authenticated-orcid":false,"given":"Si-Yang","family":"Huang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China"},{"name":"Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1186\/s13071-015-0902-6","article-title":"Diagnosis of toxoplasmosis and typing of Toxoplasma gondii","volume":"8","author":"Liu","year":"2015","journal-title":"Parasites Vectors"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1128\/CMR.05013-11","article-title":"Epidemiology of and Diagnostic Strategies for Toxoplasmosis","volume":"25","year":"2012","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"R770","DOI":"10.1016\/j.cub.2018.05.035","article-title":"Toxoplasma gondii","volume":"28","author":"Kochanowsky","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102226","DOI":"10.1016\/j.coi.2022.102226","article-title":"Immune responses to Toxoplasma gondii","volume":"77","author":"Khan","year":"2022","journal-title":"Curr. Opin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fcimb.2019.00103","article-title":"Mechanisms of Human Innate Immune Evasion by Toxoplasma gondii","volume":"9","author":"Lima","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1038\/nrmicro2858","article-title":"Modulation of innate immunity by Toxoplasma gondii virulence effectors","volume":"10","author":"Hunter","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.3389\/fimmu.2020.01709","article-title":"Toxoplasma gondii Dense Granule Proteins 7, 14, and 15 Are Involved in Modification and Control of the Immune Response Mediated via NF-\u03baB Pathway","volume":"11","author":"Ihara","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0353-9","article-title":"Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection","volume":"51","author":"Sasai","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nri3598","article-title":"Innate immunity to Toxoplasma gondii infection","volume":"14","author":"Yarovinsky","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.pt.2011.03.009","article-title":"Innate responses to Toxoplasma gondii in mice and humans","volume":"27","author":"Pifer","year":"2011","journal-title":"Trends Parasitol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Butterworth, S., Torelli, F., Lockyer, E.J., Wagener, J., Song, O.-R., Broncel, M., Russell, M.R.G., Moreira-Souza, A.C.A., Young, J.C., and Treeck, M. (2022). Toxoplasma gondii virulence factor ROP1 reduces parasite susceptibility to murine and human innate immune restriction. PLoS Pathog., 18.","DOI":"10.15252\/rc.2022113790"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/cmi.2016.12","article-title":"Innate recognition of Toxoplasma gondii in humans involves a mechanism distinct from that utilized by rodents","volume":"14","author":"Sher","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1002387","DOI":"10.3389\/fimmu.2022.1002387","article-title":"The strategies of NLRP3 inflammasome to combat Toxoplasma gondii","volume":"13","author":"Yoon","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature12306","article-title":"cGAS produces a 2\u2032-5\u2032-linked cyclic dinucleotide second messenger that activates STING","volume":"498","author":"Ablasser","year":"2013","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nature12640","article-title":"Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP","volume":"503","author":"Ablasser","year":"2013","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.molcel.2014.03.040","article-title":"The cGAS-cGAMP-STING Pathway of Cytosolic DNA Sensing and Signaling","volume":"54","author":"Cai","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular mechanisms and cellular functions of cGAS\u2013STING signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41392-020-0198-7","article-title":"The interactions between cGAS-STING pathway and pathogens","volume":"5","author":"Cheng","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41576-019-0151-1","article-title":"DNA sensing by the cGAS\u2013STING pathway in health and disease","volume":"20","author":"Motwani","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16494","DOI":"10.1074\/jbc.RA119.009172","article-title":"The GRA15 protein from Toxoplasma gondii enhances host defense responses by activating the interferon stimulator STING","volume":"294","author":"Wang","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_21","first-page":"e22171","article-title":"Toxoplasma gondii ROP18I inhibits host innate immunity through cGAS-STING signaling","volume":"36","author":"Chen","year":"2022","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1128\/IAI.01185-12","article-title":"Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15","volume":"81","author":"Jensen","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3389\/fcimb.2019.00413","article-title":"Influence of Two Major Toxoplasma Gondii Virulence Factors (ROP16 and ROP18) on the Immune Response of Peripheral Blood Mononuclear Cells to Human Toxoplasmosis Infection","volume":"9","author":"Arenas","year":"2019","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e20181757","DOI":"10.1084\/jem.20181757","article-title":"The Toxoplasma gondii virulence factor ROP16 acts in cis and trans, and suppresses T cell responses","volume":"217","author":"Chen","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e03305-20","DOI":"10.1128\/mBio.03305-20","article-title":"ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival","volume":"12","author":"Kochanowsky","year":"2021","journal-title":"mBio"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"186","DOI":"10.4049\/jimmunol.1701045","article-title":"Toxoplasma gondii Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10","volume":"200","author":"Pierog","year":"2018","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.3389\/fmicb.2017.02408","article-title":"Screening and Identification of the Host Proteins Interacting with Toxoplasma gondii Rhoptry Protein ROP16","volume":"8","author":"Pan","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/978-1-4939-6472-7_6","article-title":"Development of CRISPR\/Cas9 for Efficient Genome Editing in Toxoplasma gondii","volume":"1498","author":"Shen","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1128\/IAI.01339-13","article-title":"GRA25 Is a Novel Virulence Factor of Toxoplasma gondii and Influences the Host Immune Response","volume":"82","author":"Shastri","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e02280-14","DOI":"10.1128\/mBio.02280-14","article-title":"Toxoplasma gondii Superinfection and Virulence during Secondary Infection Correlate with the Exact ROP5\/ROP18 Allelic Combination","volume":"6","author":"Jensen","year":"2015","journal-title":"mBio"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.3389\/fimmu.2018.02073","article-title":"Toxoplasma Effector TgIST Targets Host IDO1 to Antagonize the IFN-\u03b3-Induced Anti-parasitic Response in Human Cells","volume":"9","author":"Bando","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature05395","article-title":"Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue","volume":"445","author":"Saeij","year":"2007","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"aaa2630","DOI":"10.1126\/science.aaa2630","article-title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation","volume":"347","author":"Liu","year":"2015","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/s41586-019-1228-x","article-title":"A conserved PLPLRT\/SD motif of STING mediates the recruitment and activation of TBK1","volume":"569","author":"Zhao","year":"2019","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41586-019-0998-5","article-title":"Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP\u2013AMP","volume":"567","author":"Shang","year":"2019","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1038\/cr.2016.125","article-title":"USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING\/MITA","volume":"26","author":"Zhang","year":"2016","journal-title":"Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"28646","DOI":"10.1074\/jbc.M112.362608","article-title":"TRIM32 Protein Modulates Type I Interferon Induction and Cellular Antiviral Response by Targeting MITA\/STING Protein for K63-linked Ubiquitination","volume":"287","author":"Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1038\/s41423-020-00531-5","article-title":"OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING","volume":"18","author":"Guo","year":"2020","journal-title":"Cell. Mol. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/14\/1862\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:12:33Z","timestamp":1760127153000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/14\/1862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,15]]},"references-count":39,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["cells12141862"],"URL":"https:\/\/doi.org\/10.3390\/cells12141862","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,15]]}}}