卡斯帕斯-11 裂开气皮D 进行非正规的炎症体信号传递
Nobuhiko Kayagaki1, Irma B Stowe1, Bettina L Lee1
1Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
Nature
|September 17, 2015
概括
在发生格兰阴性细菌感染后,Gasdermin D (GSDMD) 对于卡斯帕-1驱动的热和互白素-1β释放至关重要. 通过caspase-11激活GSDMD可以调解宿主对致命细菌败血症的防御.
科学领域:
- 免疫学
- 细胞生物学
- 微生物学
背景情况:
- 来自格拉姆阴性细菌的细胞内脂多糖会触发卡斯帕-11,导致热,IL-1β处理和败血症.
- 卡斯巴酶11的精确下游信号通路在很大程度上仍未被阐明.
研究的目的:
- 确定酶-11-依赖细胞死亡和细胞因子成熟的关键媒介.
- 阐明加斯德明D在宿主对细胞内阳性细菌成分的反应中的作用.
主要方法:
- 使用乙烯氨酸尿素变异的小鼠进行基因查.
- 基因向产生Gsdmd淘汰赛 (Gsdmd(-/-)) 的小鼠.
- 对巨细胞亡和IL-1β分泌的分析.
- 在脂聚糖试验后评估Gsdmd-/-) 小鼠的存活率.
主要成果:
- 鉴定Gasdermin D (Gsdmd) 对于酶11介导的热和IL-1β成熟是必不可少的.
- 在用细胞质脂多糖或格拉姆阴性细菌刺激时,巨细胞呈现缺陷的热和IL-1β分泌.
- 保护小鼠免受致死剂量的脂多糖.
- 卡斯巴-11直接切割气皮D,而N端片段会诱导热亡并激活卡斯巴-1/NLRP3炎症酶.
结论:
- 气体体D是天生的免疫反应中caspase-11的关键下游标.
- 加斯德明D调解热和IL- 1β的产生,这对抗格兰阴性细菌感染的宿主防御至关重要.
- -11-气体D轴代表了对细菌败血症的宿主防御的关键途径.
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