The molecular basis of tight nuclear tethering and inactivation of cGAS.
The molecular basis of tight nuclear tethering and inactivation of cGAS.
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DOI：
10.1038/s41586-020-2749-z
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发表时间：
2020-11
期刊：
影响因子：
64.8
通讯作者：
Li P
中科院分区：
文献类型：
--
作者：
Zhao B;Xu P;Rowlett CM;Jing T;Shinde O;Lei Y;West AP;Liu WR;Li P
病原体衍生的核酸可诱导强大的先天免疫反应。环GMP-AMP合成酶(CGAS)是一种dsDNA传感器，催化合成环状二核苷酸cGAMP，cGAMP通过STINT-TBK1-IRF3信号轴介导I型干扰素的诱导。人们普遍认为，cGAS由于其胞浆定位而不对自身DNA产生反应。然而，最近的研究表明，cGAS主要定位于细胞核中，紧密的核拴系使cGAS处于不活跃状态。在这里，我们发现cGAS以纳摩尔亲和力与核小体结合，核小体结合能有效地抑制cGAS的催化活性。为了阐明核绳系失活cGAS的分子基础，我们测定了冷冻-EM法结合人核小体的小鼠cGAS的结构。结构分析表明，cGAS通过其第二DNA结合位点与组蛋白H_2A和H_2B形成的带负电荷的酸性斑块结合。高亲和力的核小体结合阻断dsDNA结合，使cGAS保持非活性构象。破坏核小体结合的cGAS突变极大地影响了cGAS介导的细胞内信号转导。
Pathogen-derived nucleic acids induce potent innate immune responses. 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 axis. It was widely accepted that cGAS is not reactive to self-DNA due to its cytosolic localization. However, recent studies revealed that cGAS is mostly localized in the nucleus and tight nuclear tethering keeps cGAS inactive. 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 site. 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.
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影响因子：
7
作者：
Barber GN
通讯作者：
Barber GN
影响因子：
4
作者：
Wang WW;Zeng Y;Wu B;Deiters A;Liu WR
通讯作者：
Liu WR
影响因子：
32.4
作者：
Paludan SR;Bowie AG
通讯作者：
Bowie AG
环状GMP-AMP合酶通过双链DNA诱导的寡聚化激活。
影响因子：
32.4
作者：
Li, Xin;Shu, Chang;Yi, Guanghui;Chaton, Catherine T.;Shelton, Catherine L.;Diao, Jiasheng;Zuo, Xiaobing;Kao, C. Cheng;Herr, Andrew B.;Li, Pingwei
通讯作者：
Li, Pingwei
DOI：
10.1107/s2059798319011471
发表时间：
2019-10-01
影响因子：
2.2
作者：
Liebschner, Dorothee;Afonine, Pavel V.;Adams, Paul D.
通讯作者：
Adams, Paul D.