小柯机器人

美国德克萨斯A & M大学李平卫和刘文设研究组合作揭示了与核小体紧密结合环状GMP-AMP合酶（cGAS）灭活的分子基础。相关论文于2020年9月10日在线发表于国际学术期刊《自然》。

研究人员发现核小体与纳摩尔级的cGAS强烈结合，并且与核小体结合有效地抑制了cGAS的催化活性。为了阐明核小体束缚导致cGAS失活的分子基础，研究人员解析了小鼠cGAS与人核小体结合的冷冻电镜结构。

结构表明cGAS经由其第二个DNA结合位点与组蛋白H2A和H2B形成的带负电的酸性patch结合。cGAS与核小体紧密结合可阻止其结合dsDNA，并使cGAS处于非活化构象。突变cGAS与核小体结合的位点会显著影响cGAS介导的细胞信号传导。

研究人员表示，病原体核酸可诱导强烈的先天免疫反应。cGAS是细胞内dsDNA感受器，可催化环状二核苷酸cGAMP的产生，并通过STING-TBK1-IRF3信号通路诱导I型干扰素的生成。众所周知， cGAS定位于细胞质，它对自身DNA不具有反应性。但是，最近的研究表明，cGAS大部分位于核内，被核小体紧密束缚的cGAS处于非活跃状态。

附：英文原文

Title: The Molecular Basis of Tight Nuclear Tethering and Inactivation of cGAS

Author: Baoyu Zhao, Pengbiao Xu, Chesley M. Rowlett, Tao Jing, Omkar Shinde, Yuanjiu Lei, A. Phillip West, Wenshe Ray Liu, Pingwei Li

Issue&Volume: 2020-09-10

Abstract: 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.

DOI: 10.1038/s41586-020-2749-z

Source: https://www.nature.com/articles/s41586-020-2749-z

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