The DNA sensor cGAS initiates innate immune responses following microbial infection, cellular stress, and cancer 1 . Upon activation by double-stranded DNA, cytosolic cGAS produces 2’3’ cyclic GMP-AMP and triggers inflammatory cytokine and type I interferon (IFN) induction 2–7 . cGAS is also present inside the cell nucleus replete with genomic DNA 8 , where chromatin has been implicated in restricting its enzymatic activity 9 . However, the structural basis for cGAS inhibition by chromatin has remained unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes at 3.1 Å resolution. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also finds cGAS engaged to a second nucleosome in trans . Mechanistically, nucleosome binding locks cGAS in a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are necessary and sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash cGAS activity on genomic DNA in living cells. Our work uncovers the structural basis of cGAS interaction with chromatin and defines a compelling mechanism that permits self-nonself discrimination of genomic DNA by cGAS.

中文翻译：

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核小体抑制cGAS的结构机制

DNA 传感器 cGAS 在微生物感染、细胞应激和癌症 1 后启动先天免疫反应。在被双链 DNA 激活后，细胞溶质 cGAS 会产生 2'3' 环状 GMP-AMP 并触发炎症细胞因子和 I 型干扰素 (IFN) 诱导 2-7。cGAS 也存在于充满基因组 DNA 8 的细胞核内，其中染色质与限制其酶活性 9 有关。然而，染色质抑制 cGAS 的结构基础仍然未知。在这里，我们展示了以 3.1 Å 分辨率与核小体结合的人类 cGAS 的低温电子显微镜结构。cGAS 与组蛋白 H2A-H2B 异二聚体的酸性斑块和核小体 DNA 都有广泛的接触。结构和互补的生化分析还发现 cGAS 与反式的第二个核小体结合。从机制上讲，核小体结合将 cGAS 锁定在单体状态，其中空间位阻抑制基因组 DNA 的虚假激活。我们发现cGAS-酸性贴片界面的突变对于在体外消除核小体的抑制作用并释放cGAS对活细胞基因组DNA的活性是必要且足够的。我们的工作揭示了 cGAS 与染色质相互作用的结构基础，并定义了一种令人信服的机制，该机制允许 cGAS 对基因组 DNA 进行自我识别。