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

Frontiers in Immunology

Immunology

Yingke Li¹  Wanxue Song¹  Chenxi Zhang²  Chunlei Hui²  Chunlei Xing²  Juan Lv²  Dinglei Zhang²  Huihui Bian²  Liang Zhao³  Yuhong Chen⁴  Li Su⁵ 

[1]Department of Anesthesiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China

[2]Institute of Translational Medicine, Shanghai University, Shanghai, China

[3]Luodian Clinical Drug Research Center, Institute for Translational Medicine Research, Shanghai University, Shanghai, China

[4]Department of Pharmacy, Shanghai Baoshan Luodian Hospital, Shanghai, China

[5]School of Pharmacy, Bengbu Medical College, Bengbu, China

[6]Institute of Translational Medicine, Shanghai University, Shanghai, China

[7]School of Pharmacy, Bengbu Medical College, Bengbu, China

[8]Institute of Translational Medicine, Shanghai University, Shanghai, China

[9]Luodian Clinical Drug Research Center, Institute for Translational Medicine Research, Shanghai University, Shanghai, China

关键词: ubiquitination;    cecal ligation and puncture;    mice;    interferon;    septic shock;   

DOI  :  10.3389/fimmu.2023.1190707

 received in 2023-03-21, accepted in 2023-07-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Chen, Bian, Lv, Song, Xing, Hui, Zhang, Zhang, Zhao, Li and Su