刺
干扰素基因刺激剂
干扰素
内部收益率3
坦克结合激酶1
细胞生物学
小分子
信号转导衔接蛋白
促炎细胞因子
信号转导
化学
生物
受体
转录因子
炎症
基因
先天免疫系统
生物化学
免疫学
丝裂原活化蛋白激酶激酶
蛋白激酶C
工程类
航空航天工程
作者
Fiachra Humphries,Liraz Galia,Zhaozhao Jiang,Jeffrey Y. Zhou,Leonard Barasa,Santanu Mondal,Ruth Wilson,Nadia Sultana,Scott A. Shaffer,Sze‐Ling Ng,G. Scott Pesiridis,Paul R. Thompson,Katherine A. Fitzgerald
标识
DOI:10.1073/pnas.2305420120
摘要
Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhibitor of STING. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other pattern recognition receptors. In vivo, BB-Cl-amidine alleviated pathology resulting from accrual of cytosolic DNA in Trex-1 mutant mice. Mechanistically BB-Cl-amidine inhibited STING oligomerization through modification of Cys 148 . Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases.
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