Saving a host cell from itself A fundamental mammalian defense mechanism against pathogens and damaged cellular DNA is to recognize DNA fragments in the cytosol and trigger an inflammatory response. The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) that recognizes cytosolic DNA is also found in the nucleus, but here its activity is suppressed by tethering to chromatin. Two papers now report cryo–electron microscopy structures of cGAS bound to the nucleosome core particle (NCP). Kujirai et al. observed a structure with two cGAS molecules bridging two NCPs, whereas Boyer et al. observed cGAS bound to a single nucleosome. Together, these structures show how cGAS is prevented from autoreactivity toward host DNA. Science, this issue p. 455, p. 450 Structures of the cGAS-nucleosome complex reveals how chromatin inhibits cyclic GMP-AMP synthase activation. Cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory diseases, and cancer. By contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo–electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome-binding interface exclusively occupies the strong double-stranded DNA (dsDNA)–binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state. These findings provide a structural basis for how cGAS maintains an inhibited state in the nucleus and further exemplify the role of the nucleosome in regulating diverse nuclear protein functions.

中文翻译：

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核小体依赖性 cGAS 抑制的结构基础

从自身中拯救宿主细胞 哺乳动物针对病原体和受损细胞 DNA 的基本防御机制是识别细胞质中的 DNA 片段并触发炎症反应。在细胞核中也发现了识别胞质 DNA 的环状鸟苷单磷酸-腺苷单磷酸合酶 (cGAS)，但其活性被染色质束缚。现在有两篇论文报告了与核小体核心颗粒 (NCP) 结合的 cGAS 的冷冻电子显微镜结构。Kujirai 等人。观察到具有两个 cGAS 分子桥接两个 NCP 的结构，而 Boyer 等人。观察到 cGAS 与单个核小体结合。总之，这些结构显示了 cGAS 如何被阻止对宿主 DNA 的自身反应。科学，这个问题 p。455 页。450 cGAS-核小体复合物的结构揭示了染色质如何抑制环 GMP-AMP 合酶的激活。环磷酸鸟苷 (GMP)-磷酸腺苷 (AMP) 合酶 (cGAS) 可识别胞质外来或受损 DNA，以激活对感染、炎症性疾病和癌症的先天免疫反应。相比之下，染色质束缚抑制了 cGAS 对细胞核中自身 DNA 的反应。我们报告了与核小体核心颗粒复合的 cGAS 的 3.3 埃分辨率低温电子显微镜结构。该结构表明 cGAS 使用两个保守的精氨酸来锚定核小体酸性斑块。核小体结合界面仅占据 cGAS 上强双链 DNA (dsDNA) 结合表面，并在空间上阻止 cGAS 寡聚化为功能活性 2：2 cGAS-dsDNA 状态。这些发现为 cGAS 如何在细胞核中维持抑制状态提供了结构基础，并进一步举例说明了核小体在调节多种核蛋白功能中的作用。