Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Nature. 2020 Nov;587(7835):668-672. doi: 10.1038/s41586-020-2750-6. Epub 2020 Sep 10.
The DNA sensor cyclic GMP-AMP synthase (cGAS) initiates innate immune responses following microbial infection, cellular stress and cancer. Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cGMP-AMP, which triggers the induction of inflammatory cytokines and type I interferons . cGAS is also present inside the cell nucleus, which is replete with genomic DNA, where chromatin has been implicated in restricting its enzymatic activity. However, the structural basis for inhibition of cGAS by chromatin remains unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes. 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 find cGAS engaged to a second nucleosome in trans. Mechanistically, binding of the nucleosome locks cGAS into a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash the activity of cGAS on genomic DNA in living cells. Our work uncovers the structural basis of the interaction between cGAS and chromatin and details a mechanism that permits self-non-self discrimination of genomic DNA by cGAS.
DNA 传感器环鸟苷酸-腺苷酸合酶 (cGAS) 在微生物感染、细胞应激和癌症后启动先天免疫反应。在双链 DNA 的激活下，胞质 cGAS 产生 2'3' cGMP-AMP，触发炎症细胞因子和 I 型干扰素的诱导。cGAS 也存在于富含基因组 DNA 的细胞核内，染色质被认为限制了其酶活性。然而，染色质抑制 cGAS 的结构基础仍然未知。在这里，我们展示了与人 cGAS 结合核小体的低温电子显微镜结构。cGAS 与组蛋白 H2A-H2B 异二聚体的酸性斑点和核小体 DNA 都有广泛的接触。结构和互补的生化分析还发现 cGAS 与第二个核小体在转录上相互作用。从机制上讲，核小体的结合将 cGAS 锁定在单体状态，空间位阻抑制了基因组 DNA 的异常激活。我们发现，cGAS-酸性斑点界面的突变足以在体外消除核小体的抑制作用，并在活细胞中释放 cGAS 对基因组 DNA 的活性。我们的工作揭示了 cGAS 与染色质相互作用的结构基础，并详细阐述了 cGAS 对基因组 DNA 进行自我-非自我区分的机制。
