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other·immunology, preclinical research, biomedical research, critical care·PMC10424845

Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis

Frontiers in Immunology · 11 authors, 5 centres

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This preclinical study evaluated gelsevirine (GS) as a STING-specific inhibitor using in vitro macrophage assays, molecular docking, surface plasmon resonance binding, biotin pull-down assays, and a mouse cecal ligation and puncture (CLP) sepsis model. In vitro, GS potently inhibited interferon and inflammatory cytokine induction in macrophages exposed to STING agonists. Molecular studies showed GS binds with high affinity to the cyclic dinucleotide-binding pocket of STING, inhibiting dimerization and activation, and promotes K48-linked STING ubiquitination and degradation likely through TRIM21. In the CLP model, post-operative GS administration at 5 hours after surgery significantly extended survival and improved lung, liver, and kidney function. Limitations include the exclusive use of murine models with indirect clinical relevance, the need for further investigation of the TRIM21 role in STING ubiquitination, and the absence of reported quantitative survival statistics.

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other

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immunology

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ORIGINAL PAPER

PMC10424845

Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis

Frontiers in Immunology

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ABSTRACT

Abstract Background 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. Methods 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 2’3’-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. Results 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. Conclusions Our findings identify a novel STING-specific inhibitor that could be applied in the treatment of sepsis. Keywords: ubiquitination, cecal ligation and puncture, mice, interferon, septic shock

CITATION EXPORT

Yuhong Chen, Huihui Bian, Juan Lv et al.. Gelsevirine is a novel STING-specific inhibitor and mitigates STING-related inflammation in sepsis. Frontiers in Immunology. (2023). https://doi.org/10.3389/fimmu.2023.1190707

AUTHORS

11 · 5 CENTRES

Yuhong Chen, Huihui Bian, Juan Lv, Wanxue Song, Chunlei Xing, Chunlei Hui, Dinglei Zhang, Chenxi Zhang, Liang Zhao, Yingke Li, Li Su

1 School of Pharmacy, Bengbu Medical College, Bengbu, China
2 Institute of Translational Medicine, Shanghai University, Shanghai, China
3 Department of Anesthesiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China
4 Luodian Clinical Drug Research Center, Institute for Translational Medicine Research, Shanghai University, Shanghai, China
5 Department of Pharmacy, Shanghai Baoshan Luodian Hospital, Shanghai, China