紧密核连接和cGAS无活化的分子基础
Baoyu Zhao1, Pengbiao Xu1, Chesley M Rowlett2
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA.
Nature
|September 10, 2020
概括
循环GMP- AMP合成酶 (cGAS) 与核细胞结合,抑制其DNA感应活性. 这种通过冷EM揭示的相互作用解释了核定位如何使cGAS处于不活跃状态,从而影响先天免疫信号.
科学领域:
- 免疫学
- 分子生物学
- 结构生物学
背景情况:
- 源自病原体的核酸会引发天生的免疫反应.
- 循环GMP- AMP合成酶 (cGAS) 是通过STING- TBK1- IRF3途径诱导I型干扰素的关键DNA传感器.
- 最近的发现表明cGAS局部存在于核中,其活动被核结合抑制.
研究的目的:
- 通过核连接对cGAS无活化的分子机制进行研究.
- 确定cGAS与核细胞相互作用的结构基础.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定与人类核体结合的小鼠cGAS的结构.
- 生物化学测定以评估cGAS结合亲和力和催化活性.
- 使用突变cGAS进行细胞测试以研究信号效应.
主要成果:
- cGAS与高 (纳米) 亲和度的核体结合.
- 通过阻断DNA结合,核酶结合强烈抑制了cGAS的催化活性.
- 结构分析显示cGAS与基因素H2A/ H2B酸性补丁结合,保持不活跃的形状.
- 突变破坏细胞核酶结合,恢复细胞中的cGAS活性.
结论:
- 核酶结合是核中cGAS无活化的关键机制.
- 这种相互作用阻止了自我DNA的异常免疫激活.
- 了解cGAS-核酶体相互作用可以了解先天免疫调节和潜在的治疗点.
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