{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T13:47:16Z","timestamp":1793886436157,"version":"4.8.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Stimulation of IFN genes (STING) is central to the production of interferon and proinflammatory cytokines in response to microbial DNA or self-DNA in the cytosol. The detrimental role of the activation of STING during sepsis has been well documented.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we found that gelsevirine (GS) potently inhibit interferon and inflammatory cytokine induction in macrophages exposed to STING agonists (2'3'-cGAMP, IFN stimulatory DNA (ISD), and poly(dA:dT)). I n silico docking analysis and surface plasmon resonance binding study showed that GS bonds with high affinity to the cyclic dinucleotide (CDN)-binding pocket of STING. Biotin pull-down assay also confirmed that GS competitively bonded to STING protein. Furthermore, GS inhibited 2\u20193\u2019-cGAMP-induced STING dimerization and subsequent activation. In addition, GS induced K48-linked STING ubiquitination and degradation, which was likely through upregulating and recruiting TRIM21. In mice exposed to cecal ligation and puncture (CLP)-induced sepsis, post-operative administration of GS significantly extended the survival period and mitigated acute organ damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, GS inhibited STING signaling by competitively binding to the CDN-binding pocket to lock STING in an inactive open conformation, while also promoting K48-linked STING ubiquitination and degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings identify a novel STING-specific inhibitor that could be applied in the treatment of sepsis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1190707","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T16:33:29Z","timestamp":1690821209000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis"],"prefix":"10.3389","volume":"14","author":[{"given":"Yuhong","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihui","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxue","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Hui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinglei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingke","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112337","article-title":"Potential role of herbal medicines as a novel approach in sepsis treatment","volume":"144","author":"Usmani","year":"2021","journal-title":"BioMed Pharmacother"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1021\/np060156y","article-title":"Alkaloids from Gelsemium elegans","volume":"69","author":"Xu","year":"2006","journal-title":"J Nat Prod"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-012-2867-x","article-title":"The active alkaloids of Gelsemium elegans Benth. are potent anxiolytics","volume":"225","author":"Liu","year":"2013","journal-title":"Psychopharmacol (Berl)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.114975","article-title":"Gelsevirine improves age-related and surgically induced osteoarthritis in mice by reducing STING availability and local inflammation","volume":"198","author":"Feng","year":"2022","journal-title":"Biochem Pharmacol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02536","article-title":"DAMPs and NETs in sepsis","volume":"10","author":"Denning","year":"2019","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0244-x","article-title":"Molecular mechanisms and cellular functions of cGAS-STING signalling","volume":"21","author":"Hopfner","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.ebiom.2019.02.055","article-title":"STING-mediated intestinal barrier dysfunction contributes to lethal sepsis","volume":"41","author":"Hu","year":"2019","journal-title":"EBioMedicine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1038\/s41419-022-05115-x","article-title":"The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages","volume":"13","author":"Wu","year":"2022","journal-title":"Cell Death Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.chom.2020.02.004","article-title":"TMEM173 drives lethal coagulation in sepsis","volume":"27","author":"Zhang","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00999-10","article-title":"The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides","volume":"79","author":"Sauer","year":"2011","journal-title":"Infect Immun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1225-5_11","article-title":"Co-culture of human mesenchymal stromal cells and primary mouse hepatocytes","volume":"2269","author":"Hsu","year":"2021","journal-title":"Methods Mol Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.196","article-title":"Isolation and culture of neonatal murine primary cardiomyocytes","volume":"1","author":"Ravi","year":"2021","journal-title":"Curr Protoc"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-0716-1437-2_1","article-title":"General overview of neuronal cell culture","volume":"2311","author":"Gordon","year":"2021","journal-title":"Methods Mol Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3791\/56750","article-title":"Isolation, culture, and differentiation of bone marrow stromal cells and osteoclast progenitors from mice","author":"Maridas","year":"2018","journal-title":"J Vis Exp"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.95","article-title":"Primary culture and phenotyping of murine chondrocytes","volume":"3","author":"Gosset","year":"2008","journal-title":"Nat Protoc"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot5080","article-title":"Bone marrow-derived macrophages (BMM): isolation and applications","volume":"2008","author":"Weischenfeldt","year":"2008","journal-title":"CSH Protoc"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.2001.00426.x","article-title":"Induction of IRF-3\/-7 kinase and NF-kappaB in response to double-stranded RNA and virus infection: common and unique pathways","volume":"6","author":"Iwamura","year":"2001","journal-title":"Genes Cells"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.214","article-title":"Immunodesign of experimental sepsis by cecal ligation and puncture","volume":"4","author":"Rittirsch","year":"2009","journal-title":"Nat Protoc"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.097","article-title":"The cyclopeptide astin C specifically inhibits the innate immune CDN sensor STING","volume":"25","author":"Li","year":"2018","journal-title":"Cell Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009-0210ST","article-title":"An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals","volume":"44","author":"Matute-Bello","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2105465118","article-title":"STING inhibitors target the cyclic dinucleotide binding pocket","volume":"118","author":"Hong","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e3182144935","article-title":"Targeting CD44 expressed on neutrophils inhibits lung damage in abdominal sepsis","volume":"35","author":"Hasan","year":"2011","journal-title":"Shock"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050333","article-title":"Incidence and outcomes of acute lung injury","volume":"353","author":"Rubenfeld","year":"2005","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jemermed.2015.02.038","article-title":"Initial Low Oxygen Extraction Ratio Is Related to Severe Organ Dysfunction and High In-Hospital Mortality in Severe Sepsis and Septic Shock Patients","author":"Park","year":"2015","journal-title":"The Journal of emergency medicine"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01722","article-title":"Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury","volume":"11","author":"Kumar","year":"2020","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nrgastro.2016.168","article-title":"Liver - guardian, modifier and target of sepsis","volume":"14","author":"Strnad","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.tim.2011.01.001","article-title":"Cecal ligation and puncture: the gold standard model for polymicrobial sepsis","volume":"19","author":"Dejager","year":"2011","journal-title":"Trends Microbiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-021-06506-y","article-title":"\u201cSurviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.\u201d","volume":"47","author":"Evan","year":"2021","journal-title":"Intensive care medicine"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00703","article-title":"TRIM21 aggravates herpes simplex virus epithelial keratitis by attenuating STING-IRF3-mediated type I interferon signaling","volume":"11","author":"Tan","year":"2020","journal-title":"Front Microbiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0287-8","article-title":"Targeting STING with covalent small-molecule inhibitors","volume":"559","author":"Haag","year":"2018","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.8b00466","article-title":"Discovery of a novel cGAMP competitive ligand of the inactive form of STING","volume":"10","author":"Siu","year":"2018","journal-title":"ACS Med Chem Lett"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806239115","article-title":"Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling","volume":"115","author":"Hansen","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1084\/jem.20151531","article-title":"Ubiquitin in the activation and attenuation of innate antiviral immunity","volume":"213","author":"Heaton","year":"2016","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/cells3030848","article-title":"Bacterial effectors and their functions in the ubiquitin-proteasome system: insight from the modes of substrate recognition","volume":"3","author":"Kim","year":"2014","journal-title":"Cells"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cells8010002","article-title":"The role of ATG16 in autophagy and the ubiquitin proteasome system","volume":"8","author":"Xiong","year":"2018","journal-title":"Cells"},{"key":"B38","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.tibs.2017.01.002","article-title":"TRIM family proteins: roles in autophagy, immunity, and carcinogenesis","volume":"42","author":"Hatakeyama","year":"2017","journal-title":"Trends Biochem Sci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1146\/annurev-virology-092917-043323","article-title":"TRIM proteins and their roles in antiviral host defenses","volume":"5","author":"van Gent","year":"2018","journal-title":"Annu Rev Virol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/j.celrep.2019.09.069","article-title":"STING-mediated IFI16 degradation negatively controls type I interferon production","volume":"29","author":"Li","year":"2019","journal-title":"Cell Rep"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2492","article-title":"The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA","volume":"14","author":"Zhang","year":"2013","journal-title":"Nat Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1190707\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T16:33:32Z","timestamp":1690821212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1190707\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,31]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2023.1190707"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1190707","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,31]]},"article-number":"1190707"}}