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通过防止细胞死亡和使血液形成成为可能,LUBAC对于胚胎形成至关重要

Nieves Peltzer¹, Maurice Darding¹, Antonella Montinaro¹

¹UCL Cancer Institute, University College London, London, UK.

|April 27, 2018

概括

HOIL-1 对于线性泛素链组合复合体 (LUBAC) 功能至关重要,确保正确的组合和稳定性,以防止胚胎发生期间的异常细胞死亡. 缺少HOIL-1会导致胚胎死亡,这突显了它与HOIP一起在LUBAC介导的TNFR1信号传递中的重要作用.

科学领域:

分子生物学
免疫学
发育生物学

背景情况:

线性泛素链组合复合体 (LUBAC) 对免疫受体信号,特别是TNFR1至关重要,影响基因激活和细胞死亡.
在小鼠中,LUBAC成分如SHARPIN和HOIP的缺乏导致严重的炎症或胚胎死亡.
人类的HOIL-1缺乏导致炎症性疾病,但其在小鼠中的作用以前尚不清楚.

研究的目的:

研究HOIL-1在LUBAC功能中的重要作用及其对胚胎发生的影响.
阐明HOIL-1对LUBAC组装,稳定性和TNFR1信号的具体机制.
了解胚胎发育期间涉及HOIL-1,HOIP,RIPK1,RIPK3,MLKL和caspase-8的补偿途径和遗传相互作用.

主要方法:

产生和分析缺乏HOIL-1的小鼠 (Hoil-1-/-或Rbck1-/-).
涉及关键细胞死亡途径组件 (RIPK1,RIPK3,MLKL,caspase-8) 的遗传操纵.
在淘汰模式中评估胚胎死亡率,细胞死亡途径和造血发育.

主要成果:

HOIL-1 对于 LUBAC 组合,稳定性和 TNFR1 复合物的保留至关重要,防止异常细胞死亡.
通过部分依赖RIPK1的TNFR1介导的内皮细胞死亡,HOIL-1和HOIP都能预防妊娠中期的胚胎死亡.
活跃的HOIL-1缺乏的小鼠需要联合删除caspase-8和MLKL;然而,三重淘汰 (Ripk3-/-Casp8-/-Hoil-1-/-) 由于由RIPK1删除所拯救的造血缺陷而死亡.

结论:

与HOIP一样,HOIL-1对于LUBAC功能和胚胎发生是不可或缺的,因为它可以防止异常细胞死亡.
在没有LUBAC和caspase-8的情况下,RIPK3充当关键调节剂,防止RIPK1诱导的胚胎致死性.

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