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. The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo–electron microscopy structure of the human cGAS–nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.

中文翻译：

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核小体抑制 cGAS 的结构基础

从自身拯救宿主细胞 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。现在有两篇论文报道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 发生自身反应。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-磷酸腺苷合酶 (cGAS) 感知病原 DNA 的入侵并刺激炎症信号、自噬和细胞凋亡。提议将宿主 DNA 组织成核小体以限制 cGAS 的自诱导，但潜在机制尚不清楚。在这里，我们报告了这种抑制的结构基础。在人 cGAS-核小体核心颗粒 (NCP) 复合物的冷冻电子显微镜结构中，两个 cGAS 单体通过结合组蛋白 H2A-H2B 二聚体和核小体 DNA 的酸性斑块来桥接两个 NCP。在这种配置中，cGAS 激活所需的所有三个已知 cGAS DNA 结合位点都被重新利用或变得不可访问，cGAS 二聚化、激活的另一个先决条件是禁止。突变连接 cGAS 和酸性斑块的关键残基可减轻核小体抑制。这项研究为 cGAS 在染色质化的自身 DNA 上沉默的原因建立了一个结构框架。