炎症性卡斯帕斯的GSDMD裂变决定了热细胞死亡
Jianjin Shi1,2, Yue Zhao2, Kun Wang2
1Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, 100084, China.
Nature
|September 17, 2015
概括
炎症性卡斯帕斯通过分裂关键免疫蛋白质气体皮质D (GSDMD) 来激活活体. 这种裂变释放了GSDMD
科学领域:
- 免疫学
- 细胞生物学
- 分子机制
背景情况:
- 炎症性卡斯帕斯 (卡斯帕斯-1, -4, -5, -11) 对于天生的免疫力至关重要,并触发热.
- 炎症性卡斯帕斯诱导热的确切机制在很大程度上是未知的.
研究的目的:
- 为了阐明炎症性卡斯帕斯诱导热的分子机制.
- 确定介导-1和-1诱导的关键宿主因子.
主要方法:
- 在小鼠骨髓巨中进行全基因组CRISPR-Cas9选.
- 在GSDMD缺乏的细胞中对热致死诱导和介质蛋白-1β释放的分析.
- 生物化学测试以确定气体皮质蛋白家族的炎症性裂点.
主要成果:
- 鉴定出Gasdermin D (GSDMD) 是热的关键调解剂.
- 缺乏GSDMD的细胞对由LPS和炎症体连接体诱导的烧死具有抗性.
- 卡斯帕-1和卡斯帕-4/5/11特别分裂GSDMD,释放其诱导热的N终端域.
- 在GSDMA3中获得功能的突变也显示了其N终端域的炎症诱导活性.
结论:
- GSDMD是炎症性卡斯巴酶中介性炎症的直接执行者.
- 炎症性体对GSDMD的裂变是必不可少的,并且足以引起热.
- 这些发现提供了炎症体,体和编程细胞死亡之间的机制联系.
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