通过染色体对cGAS的封存和自身抑制的结构基础
Sebastian Michalski1,2, Carina C de Oliveira Mann1,2, Che A Stafford1,2
1Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.
Nature
|September 10, 2020
概括
在细胞核中封存并抑制循环GMP- AMP合成酶 (cGAS). 这种涉及基因素和酸性补丁的相互作用阻止cGAS与DNA结合并启动自身免疫反应.
科学领域:
- 免疫学
- 分子生物学
- 结构生物学
背景情况:
- 循环GMP-AMP合成酶 (cGAS) 是检测细胞核DNA的关键先天免疫传感器.
- cGAS激活导致STING介导的免疫反应,但它也可以准自身DNA,从而导致自身免疫.
- 最近的研究表明cGAS定位在核中,需要防止自我DNA识别的机制.
研究的目的:
- 阐明核cGAS被染色体隔离和抑制的机制.
- 了解染色体结合如何阻止cGAS对核自我DNA的自动反应.
主要方法:
- 电子显微镜测定结合于核体的cGAS的结构.
- 生物化学测试以评估DNA和核细胞对cGAS的竞争性结合.
主要成果:
- 一个冷EM结构揭示了cGAS与核素的酸性补丁中的2A-2B结合,而不是DNA.
- 这种相互作用会阻断cGAS的DNA结合部位B,从而抑制二聚体的形成和活性.
- 核的酸性补丁有效地超越了DNA的cGAS结合,即使在活跃的基因组区域附近.
结论:
- 通过与核细胞组组基因子和酸性补丁的相互作用,核cGAS被染色体主动隔离和抑制.
- 这种由染色质介导的抑制是防止核自我DNA自动反应的关键机制.
- 了解这种相互作用可以了解免疫调节和自身免疫性疾病.
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