cGAS is activated by DNA in a length-dependent manner
cGAS is activated by DNA in a length-dependent manner
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DOI：
10.15252/embr.201744017
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发表时间：
2017-10-01
期刊：
影响因子：
7.7
通讯作者：
Paludan, Soren R.
中科院分区：
文献类型：
--
作者：
Luecke, Stefanie;Holleufer, Andreas;Paludan, Soren R.
胞质DNA刺激先天性免疫应答，包括具有抗病毒和免疫调节活性的I型干扰素（IFN）。环GMP-AMP合酶（cGAS）识别细胞质DNA并通过STING发出信号以诱导IFN产生。尽管DNA在先天免疫中的重要性，但刺激IFN产生的DNA的性质并没有得到很好的描述。使用低DNA浓度，我们表明，dsDNA诱导IFN的长度依赖性的方式。这在DNA的宽长度跨度上观察到，范围从最小刺激长度到几种酶，并且完全依赖于cGAS，而与DNA长度无关。重要的是，体外研究表明，长DNA比短DNA更有效地激活重组人cGAS，这表明长度依赖性DNA识别是cGAS的固有特性，不依赖于辅助蛋白。总的来说，这项工作将长DNA鉴定为在细胞溶质DNA挑战如病毒感染时刺激cGAS途径的分子实体。
Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities. Cyclic GMP-AMP synthase (cGAS) recognizes cytoplasmic DNA and signals via STING to induce IFN production. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Using low DNA concentrations, we show that dsDNA induces IFN in a length-dependent manner. This is observed over a wide length-span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Importantly, in vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length-dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections.