Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA.
Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA.
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DOI：
10.1038/ni.3267
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发表时间：
2015-10
影响因子：
30.5
通讯作者：
Schlee M
中科院分区：
文献类型：
--
作者：
Herzner AM;Hagmann CA;Goldeck M;Wolter S;Kübler K;Wittmann S;Gramberg T;Andreeva L;Hopfner KP;Mertens C;Zillinger T;Jin T;Xiao TS;Bartok E;Coch C;Ackermann D;Hornung V;Ludwig J;Barchet W;Hartmann G;Schlee M
逆转录病毒或 DNA 病毒感染期间出现的胞质 DNA 会引发抗病毒 I 型干扰素反应。到目前为止，只有长度超过 40 个碱基对 (bp) 的双链 DNA (dsDNA) 被认为具有免疫刺激作用。在这里，我们发现，短碱基对 DNA 延伸侧翼的未配对 DNA 核苷酸（如源自 1 型人类免疫缺陷病毒 (HIV-1) 的单链 DNA (ssDNA) 的茎环结构）以序列依赖性方式激活 I 型干扰素诱导 DNA 传感器 cGAS。侧翼含有未配对鸟苷的短（12 至 20 bp）dsDNA（Y 型 DNA）的 DNA 结构具有高度刺激性，并且特异性增强 cGAS 的酶活性。此外，我们发现初级 HIV-1 逆转录物代表了巨噬细胞早期感染期间的主要病毒胞质 DNA 种类，并且这些 ssDNA 具有高度免疫刺激性。总的来说，我们的研究将 Y 型 DNA 中未配对的鸟苷鉴定为一种高度活跃、最小的 cGAS 识别基序，能够检测 HIV-1 ssDNA。
Cytosolic DNA that emerges during infection with a retrovirus or DNA virus triggers antiviral type I interferon responses. So far, only double-stranded DNA (dsDNA) over 40 base pairs (bp) in length has been considered immunostimulatory. Here we found that unpaired DNA nucleotides flanking short base-paired DNA stretches, as in stem-loop structures of single-stranded DNA (ssDNA) derived from human immunodeficiency virus type 1 (HIV-1), activated the type I interferon–inducing DNA sensor cGAS in a sequence-dependent manner. DNA structures containing unpaired guanosines flanking short (12- to 20-bp) dsDNA (Y-form DNA) were highly stimulatory and specifically enhanced the enzymatic activity of cGAS. Furthermore, we found that primary HIV-1 reverse transcripts represented the predominant viral cytosolic DNA species during early infection of macrophages and that these ssDNAs were highly immunostimulatory. Collectively, our study identifies unpaired guanosines in Y-form DNA as a highly active, minimal cGAS recognition motif that enables detection of HIV-1 ssDNA.