Gelsevirine 是一种新型 STING 特异性抑制剂，可减轻脓毒症中与 STING 相关的炎症,Frontiers in Immunology

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Gelsevirine 是一种新型 STING 特异性抑制剂，可减轻脓毒症中与 STING 相关的炎症
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2023-07-31 , DOI: 10.3389/fimmu.2023.1190707
Yuhong Chen _{1,

2} , Huihui Bian ₂ , Juan Lv ₂ , Wanxue Song ₃ , Chunlei Xing ₂ , Chunlei Hui ₂ , Dinglei Zhang ₂ , Chenxi Zhang ₂ , Liang Zhao _{4,

5} , Yingke Li ₃ , Li Su _{1,

2,

4}

Affiliation

背景刺激干扰素基因 (STING) 对于响应细胞质中的微生物 DNA 或自身 DNA 产生干扰素和促炎细胞因子至关重要。败血症期间 STING 激活的有害作用已得到充分证明。方法在这里，我们发现gelsevirine (GS) 有效抑制暴露于 STING 激动剂（2'3'-cGAMP、IFN 刺激性 DNA (ISD) 的巨噬细胞中的干扰素和炎症细胞因子诱导。 ) 和聚(dA:dT))。计算机对接分析和表面等离子共振结合研究表明，GS 以高亲和力与 STING 的环状二核苷酸 (CDN) 结合袋结合。生物素下拉分析也证实 GS 与 STING 蛋白竞争性结合。此外，GS 抑制 2'3'-cGAMP 诱导的 STING 二聚化和随后的激活。此外，GS 诱导 K48 连接的 STING 泛素化和降解，这可能是通过上调和招募 TRIM21 实现的。在暴露于盲肠结扎穿刺 (CLP) 诱导的脓毒症的小鼠中，术后给予 GS 显着延长了生存期并减轻了急性器官损伤。结果总体而言，GS 通过竞争性结合 CDN 结合袋锁定 STING 来抑制 STING 信号传导处于非活性开放构象，同时还促进 K48 连接的 STING 泛素化和降解。结论我们的研究结果确定了一种新型 STING 特异性抑制剂，可用于治疗脓毒症。

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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 (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.

更新日期：2023-07-31

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