Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis
BackgroundStimulation 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.MethodsHere, we found that gelsevirine (...
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| Format: | Article |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1190707/full |
| _version_ | 1797768532421771264 |
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| author | Yuhong Chen Yuhong Chen Huihui Bian Juan Lv Wanxue Song Chunlei Xing Chunlei Hui Dinglei Zhang Chenxi Zhang Liang Zhao Liang Zhao Yingke Li Li Su Li Su Li Su |
| author_facet | Yuhong Chen Yuhong Chen Huihui Bian Juan Lv Wanxue Song Chunlei Xing Chunlei Hui Dinglei Zhang Chenxi Zhang Liang Zhao Liang Zhao Yingke Li Li Su Li Su Li Su |
| author_sort | Yuhong Chen |
| collection | DOAJ |
| description | BackgroundStimulation 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.MethodsHere, 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 2’3’-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.ResultsOverall, 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.ConclusionsOur findings identify a novel STING-specific inhibitor that could be applied in the treatment of sepsis. |
| first_indexed | 2024-03-12T20:54:43Z |
| format | Article |
| id | doaj.art-0679c651868e42c6b191edda549e42ee |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T20:54:43Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0679c651868e42c6b191edda549e42ee2023-07-31T16:30:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-07-011410.3389/fimmu.2023.11907071190707Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsisYuhong Chen0Yuhong Chen1Huihui Bian2Juan Lv3Wanxue Song4Chunlei Xing5Chunlei Hui6Dinglei Zhang7Chenxi Zhang8Liang Zhao9Liang Zhao10Yingke Li11Li Su12Li Su13Li Su14School of Pharmacy, Bengbu Medical College, Bengbu, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaDepartment of Anesthesiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaLuodian Clinical Drug Research Center, Institute for Translational Medicine Research, Shanghai University, Shanghai, ChinaDepartment of Pharmacy, Shanghai Baoshan Luodian Hospital, Shanghai, ChinaDepartment of Anesthesiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, ChinaSchool of Pharmacy, Bengbu Medical College, Bengbu, ChinaInstitute of Translational Medicine, Shanghai University, Shanghai, ChinaLuodian Clinical Drug Research Center, Institute for Translational Medicine Research, Shanghai University, Shanghai, ChinaBackgroundStimulation 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.MethodsHere, 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 2’3’-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.ResultsOverall, 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.ConclusionsOur findings identify a novel STING-specific inhibitor that could be applied in the treatment of sepsis.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1190707/fullubiquitinationcecal ligation and puncturemiceinterferonseptic shock |
| spellingShingle | Yuhong Chen Yuhong Chen Huihui Bian Juan Lv Wanxue Song Chunlei Xing Chunlei Hui Dinglei Zhang Chenxi Zhang Liang Zhao Liang Zhao Yingke Li Li Su Li Su Li Su Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis Frontiers in Immunology ubiquitination cecal ligation and puncture mice interferon septic shock |
| title | Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis |
| title_full | Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis |
| title_fullStr | Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis |
| title_full_unstemmed | Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis |
| title_short | Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis |
| title_sort | gelsevirine is a novel sting specific inhibitor and mitigates sting related inflammation in sepsis |
| topic | ubiquitination cecal ligation and puncture mice interferon septic shock |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1190707/full |
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