在发育过程中,RIPK1抑制ZBP1驱动的亡
Kim Newton1, Katherine E Wickliffe1, Allie Maltzman1
1Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
Nature
|November 8, 2016
概括
与受体相互作用的蛋白激酶1 (RIPK1) 通常阻止Z-DNA结合蛋白1 (ZBP1) 激活RIPK3依赖性亡. RIPK1的损失
科学领域:
- 细胞生物学
- 免疫学
- 细胞死亡的分子机制
背景情况:
- 受体相互作用蛋白激酶1 (RIPK1) 对于细胞存活至关重要,因为RIPK1缺乏导致由于异常亡和亡的围产期死亡.
- 虽然催化不活跃的RIPK1突变允许生存,这表明它具有支架功能,但RIPK1在调节细胞死亡途径中的确切作用仍然不完全理解.
- RIP同型相互作用基因 (RHIM) 是RIPK1中的一个关键域,参与细胞死亡信号中的蛋白质-蛋白质相互作用.
研究的目的:
- 研究受体相互作用蛋白激酶1 (RIPK1) 的RIP同型相互作用动机 (RHIM) 在预防发育过程中的细胞死亡中的作用.
- 为了阐明RIPK1,Z-DNA结合蛋白1 (ZBP1) 和RIPK3在亡调节的背景下之间的相互作用.
- 确定ZBP1介导的RIPK3激活是否有助于RIPK1功能受损的小鼠的死亡率.
主要方法:
- 产生和分析RIPK1RHIM/RHIM小鼠与突变的RIPK1RHIM残留物.
- 在基因改造小鼠模型中评估亡标记 (RIPK3自化) 和致死性 (例如,Ripk3淘汰赛,MLKL淘汰赛).
- 共同免疫沉试验用于研究ZBP1和RIPK3在各种遗传背景中的蛋白质相互作用.
主要成果:
- 具有突变RHIM (Ripk1RHIM/ RHIM) 的表达RIPK1的小鼠表现出围产期致死性和RIPK3自化,表明死亡.
- 通过RIPK3或MLKL的遗传缺陷或通过使用催化不活的RIPK3阻止死亡,在Ripk1RHIM/RHIM小鼠中挽救死亡.
- 在没有功能性的RIPK1和MLKL的情况下,ZBP1与RIPK3相互作用.
结论:
- RIPK1的RHIM域作为一个关键车,防止ZBP1在发育过程中不适当地参与RIPK3并启动亡.
- ZBP1- RIPK3- MLKL依赖性亡是一种关键途径,必须被RIPK1抑制以实现正常的胚胎和围产期生存.
- 这些发现揭示了RIPK1 RHIM在通过控制ZBP1介导的死细胞信号传递来保护发育中的新型抑制作用.
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