细胞质 DNA 传感器 cGAS 促进了基因细胞死亡
Christian Zierhut1, Norihiro Yamaguchi2, Maria Paredes1
1Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
Cell
|July 13, 2019
概括
核细胞在线分裂过程中抑制了干扰素基因 (STING) 循环GMP-AMP合成酶 (cGAS) 刺激途径. 异常的线粒分裂会触发cGAS-STING依赖的IRF3酸化,诱导细胞亡并增强抗癌药物反应.
科学领域:
- 免疫学
- 细胞生物学
- 癌症研究
背景情况:
- 通过循环GMP-AMP合成酶 (cGAS) 刺激干扰素基因 (STING) 途径感知细胞质DNA通常会诱导炎症.
- 基因分裂过程中染色体DNA激活cGAS-STING的作用尚不清楚.
- 核是已知的DNA可访问性和细胞过程的调节者.
研究的目的:
- 调查在线粒分裂过程中暴露cGAS对染色体DNA的功能后果.
- 要确定cGAS-STING通路在正常或异常的线粒分裂过程中是否被激活.
- 探索在癌症治疗中准cGAS-STING途径的潜力.
主要方法:
- 通过生物化学测试评估线粒分裂过程中的cGAS-STING通路激活.
- 研究核体在抑制cGAS活动中的作用.
- 分析IRF3酸化及其下游对亡的影响.
- 在临床前模型和患者数据中评估cGAS和IRF3表达对瘤抗菌剂反应的影响.
主要成果:
- 核细胞组竞争性地抑制了依赖于DNA的cGAS激活,在正常的线粒分裂过程中阻止了有效的cGAS-STING通路激活.
- 线粒体停止导致cGAS依赖的IRF3酸化缓慢积累,而不会引起炎症.
- 化IRF3通过促进线粒体外膜透,独立于其DNA结合域诱导亡.
- 通过表达cGAS和IRF3,可以提高癌细胞和异种植的瘤对Taxol等抗菌素药物的反应.
- 在非小细胞肺癌中,TCGA数据表明cGAS表达与分类因子反应之间存在相关性.
结论:
- 在正常的线粒分裂过程中,cGAS-STING通路被核子体积极抑制.
- 在线粒异常期间累积的化IRF3会触发转录独立的亡.
- 当在癌细胞中表达时,cGAS-STING途径可以使瘤对抗菌因疗法敏感,从而提供一种潜在的治疗策略.
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