Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
EMBO Rep. 2017 Oct;18(10):1707-1715. doi: 10.15252/embr.201744017. Epub 2017 Aug 10.
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, 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.
细胞质 DNA 刺激先天免疫反应，包括具有抗病毒和免疫调节活性的 I 型干扰素（IFN）。环鸟苷酸-腺苷酸合酶（cGAS）识别细胞质 DNA，并通过 STING 信号诱导 IFN 产生。尽管 DNA 在先天免疫中很重要，但刺激 IFN 产生的 DNA 的性质尚不清楚。我们使用低浓度的 DNA 表明 dsDNA 以长度依赖性方式诱导 IFN。这在从最小刺激长度到几千个碱基的广泛长度范围内都能观察到，并且完全依赖于 cGAS，而与 DNA 长度无关。重要的是，研究表明长 DNA 比短 DNA更有效地激活重组人 cGAS，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，这项工作确定了长 DNA 作为分子实体，在病毒感染等细胞质 DNA 挑战时刺激 cGAS 途径。
