RIPK1对抗ZBP1介导的亡,以抑制炎症
Juan Lin1, Snehlata Kumari1, Chun Kim1
1Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
Nature
|November 8, 2016
概括
通过抑制Z-DNA结合蛋白1 (ZBP1) 诱导的亡,防止皮肤炎症和胚胎死亡. 这项研究揭示了RIPK1在预防ZBP1介导的细胞死亡和炎症方面的关键作用.
科学领域:
- 细胞生物学
- 免疫学
- 发育生物学
背景情况:
- 与受体相互作用的蛋白激酶1 (RIPK1) 在调节细胞死亡和炎症方面具有双重作用.
- RIPK1的酶活性促进了亡和亡,而其酶独立的功能对发育和屏障完整性至关重要.
- 在此之前,RIPK1抑制RIPK3- MLKL介导的亡的机制是未知的.
研究的目的:
- 阐明RIPK1防止RIPK3-MLKL依赖性亡的机制.
- 研究RIPK1在Z-DNA结合蛋白1 (ZBP1) 介导的皮肤炎症和胚胎发育中的作用.
主要方法:
- 使用表皮特异性的RIPK1淘汰小鼠和突变RIPK1 (RIPK1mRHIM) 的小鼠.
- 在基因改造小鼠模型中评估了角质细胞亡,皮肤炎症和围产死亡率.
- 使用细胞测试研究了RIPK1,RIPK3和ZBP1之间的蛋白质相互作用.
主要成果:
- 通过抑制ZBP1诱导的RIPK3和MLKL激活,RIPK1可以预防皮肤炎症.
- RIPK1的RHIM域的突变导致围产期死亡和皮肤炎症,由RIPK3,MLKL或ZBP1的缺陷挽救.
- 发现RIPK1的RHIM域可以阻止ZBP1与RIPK3结合.
结论:
- RIPK1 抑制ZBP1诱导的亡,从而防止围产死亡和皮肤炎症.
- ZBP1被认为是炎症的关键媒介,其已知的功能超出了抗病毒防御范围.
- ZBP1的调节失调可能会导致亡相关的炎症性疾病.
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