Pathogen-derived nucleic acids induce potent innate immune responses1-6. Cyclic GMP-AMP synthase (cGAS) is a dsDNA sensor that catalyzes the synthesis of a cyclic dinucleotide cGAMP, which mediates the induction of type I interferons through the STING-TBK1-IRF3 signaling axis7-11. It was widely accepted that cGAS is not reactive to self-DNA due to its cytosolic localization2,12,13. However, recent studies revealed that cGAS is mostly localized in the nucleus and tight nuclear tethering keeps cGAS inactive14-18. Here we show that cGAS binds to nucleosomes with nanomolar affinity and nucleosome binding potently inhibits the catalytic activity of cGAS. To elucidate the molecular basis of cGAS inactivation by nuclear tethering, we have determined the structure of mouse cGAS bound to human nucleosome by cryo-EM. The structure shows that cGAS binds to a negatively charged acidic patch formed by histone H2A and H2B via its second DNA binding site19. High affinity nucleosome binding blocks dsDNA binding and keeps cGAS in an inactive conformation. Mutations of cGAS that disrupt nucleosome binding dramatically affect cGAS mediated signaling in cells.

中文翻译：

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紧密核束缚和 cGAS 失活的分子基础

病原体衍生的核酸诱导有效的先天免疫反应1-6。环状 GMP-AMP 合酶 (cGAS) 是一种 dsDNA 传感器，可催化环状二核苷酸 cGAMP 的合成，通过 STING-TBK1-IRF3 信号轴 7-11 介导 I 型干扰素的诱导。人们普遍认为，cGAS 由于其胞质定位2、12、13 而对自身 DNA 没有反应。然而，最近的研究表明，cGAS 主要位于细胞核中，并且紧密的核束缚使 cGAS 保持无活性 14-18。在这里，我们显示 cGAS 以纳摩尔亲和力与核小体结合，并且核小体结合有效地抑制 cGAS 的催化活性。为了阐明核束缚导致 cGAS 失活的分子基础，我们通过冷冻电镜确定了与人核小体结合的小鼠 cGAS 的结构。该结构表明，cGAS 通过其第二个 DNA 结合位点与组蛋白 H2A 和 H2B 形成的带负电荷的酸性斑块结合。高亲和力核小体结合阻断 dsDNA 结合并使 cGAS 保持非活性构象。破坏核小体结合的cGAS突变显着影响细胞中cGAS介导的信号传导。