Species-specific detection of the antiviral small-molecule compound CMA by STING
Species-specific detection of the antiviral small-molecule compound CMA by STING
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DOI：
10.1038/emboj.2013.86
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发表时间：
2013-05-15
期刊：
影响因子：
11.4
通讯作者：
Hornung, Veit
中科院分区：
文献类型：
--
作者：
Cavlar, Taner;Deimling, Tobias;Hornung, Veit
自20世纪70年代初开始的对抗病毒小分子的广泛研究已确定10 - 羧甲基 - 9 - 吖啶酮（CMA）是一种有效的I型干扰素（IFN）诱导剂。到目前为止，这种抗病毒分子的作用机制仍然不清楚。在此我们证明，CMA介导一种细胞内在的I型干扰素反应，这依赖于内质网驻留蛋白STING。CMA直接与STING结合，并通过TBK1/IRF3途径引发强烈的抗病毒反应。有趣的是，虽然CMA在小鼠系统中显示出对IRF3磷酸化的非凡活性，但CMA无法激活对STING配体有反应的人类细胞。这种无法激活人类STING的情况可归因于它无法与人类STING的C末端配体结合域结合。晶体学研究表明，两个CMA分子与STING二聚体的中央环二鸟苷酸（c - diGMP）结合口袋结合，并以一种与c - diGMP相似但部分不同的方式折叠盖子区域。总之，这些结果为STING的配体感应特性提供了新的见解，此外，还揭示了这种先天传感器出乎意料的物种特异性差异。
Extensive research on antiviral small molecules starting in the early 1970s has led to the identification of 10-carboxymethyl-9-acridanone (CMA) as a potent type I interferon (IFN) inducer. Up to date, the mode of action of this antiviral molecule has remained elusive. Here we demonstrate that CMA mediates a cell-intrinsic type I IFN response, depending on the ER-resident protein STING. CMA directly binds to STING and triggers a strong antiviral response through the TBK1/IRF3 route. Interestingly, while CMA displays extraordinary activity in phosphorylating IRF3 in the murine system, CMA fails to activate human cells that are otherwise responsive to STING ligands. This failure to activate human STING can be ascribed to its inability to bind to the C-terminal ligand-binding domain of human STING. Crystallographic studies show that two CMA molecules bind to the central Cyclic diguanylate (c-diGMP)-binding pocket of the STING dimer and fold the lid region in a fashion similar, but partially distinct, to c-diGMP. Altogether, these results provide novel insight into ligand-sensing properties of STING and, furthermore, unravel unexpected species-specific differences of this innate sensor.