卡斯巴8的活性决定了细胞死亡途径之间的可塑性
Kim Newton1, Katherine E Wickliffe2, Allie Maltzman2
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. knewton@gene.com.
Nature
|November 15, 2019
概括
不活跃的caspase-8 (CASP8) 通过激活caspase-1和caspase-11通路引发致命的炎症,即使死亡细胞被阻断. 这揭示了细胞死亡途径的意想不到的可塑性.
科学领域:
- 细胞生物学
- 免疫学
- 分子生物学
背景情况:
- 卡斯巴酶具有双重作用,调解亡和抑制亡.
- 缺乏功能性caspase-8的小鼠表现出胚胎致死性,
研究的目的:
- 为了研究非活跃的Caspase-8的支持死亡的功能.
- 阐明在被抑制的-8和MLKL小鼠中观察到的致死性背后的分子机制.
主要方法:
- 使用了基因改造的小鼠模型 (Casp8 ((C362A),Mlkl-/-,Casp1-/-,Asc-/-,Casp11-/).
- 分析了GSDMD和下游caspases的卡斯帕斯-1依赖裂变.
- 检查了肠道组织中的ASC斑块形成和caspase-11升高调节.
主要成果:
- 在MLKL缺乏的小鼠中,非活跃的caspase-8 (CASP8(C362A)) 诱导了ASC点的形成和caspase-1依赖的GSDMD,caspase-3和caspase-7的裂变.
- Caspase-1和ASC对周围死亡表型至关重要.
- 卡斯巴酶11的升级也导致了死亡率.
- RIPK3 独立于死细胞的功能也导致了死亡.
结论:
- 不活跃的caspase-8具有促死亡的支架功能,可以激活炎症性caspases (caspase-1和caspase-11).
- 这一途径涉及ASC斑点形成和GSDMD裂变,导致产周死亡.
- 这项研究揭示了细胞死亡途径的显著可塑性,这对了解炎症性疾病有意义.
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