PARP5A和RNF146相分离抑制了RIPK1-依赖性亡
Shouqiao Hou1, Jian Zhang2, Xiaoyan Jiang3
1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 101408, China.
Molecular cell
|January 25, 2024
概括
阶段分离调节亡,这是细胞死亡的途径. PARP5A和RNF146形成凝结物,使RIPK1无处不在,抑制细胞的编程死亡.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 阶段分离驱动生物分子凝结物的形成和功能.
- 亡,一种涉及RIPK1,RIPK3和MLKL的编程细胞死亡途径,与人类疾病有关.
- 通过相位分离调节亡的过程仍然未被探索.
研究的目的:
- 为了调查死细胞灭绝是否通过相位分离来调节.
- 阐明PARP5A和RNF146在亡中的作用.
- 为了确定控制RIPK1在亡过程中的活性的分子机制.
主要方法:
- 在小鼠胚胎纤维细胞中诱导亡.
- 通过TAX1BP1.1.6招募PARP5A和RNF146.
- 分析类似液体的冷凝物形成和多价值物相互作用.
- 对RIPK1.1的多ADP-ribosylation (PARylation) 和PARylation-dependent ubiquitination (PARdU) 的评价进行了评估.
- 对RIPK1 (K376) 的特定部位的无处不在分析.
- 评估RIPK1的蛋白质体降解及其对死的影响.
主要成果:
- 在死亡诱导过程中,PARP5A和RNF146形成类似液体的凝结物.
- 这些凝结物介于激活RIPK1.1的PARylation和PARylation-dependent ubiquitination (PARdU) 中介.
- PARdU主要发生在小鼠RIPK1.1的K376残留物上.
- 这种无处不在促进了激酶激活RIPK1的蛋白质体降解,从而抑制了亡.
- 死体亡的相分离依赖性控制由PARP5A和RNF146.6进行介导.
结论:
- 阶段分离是死的调节机制.
- PARP5A和RNF146形成了控制RIPK1活动的功能凝聚物.
- 在K376处RIPK1的PARylation-dependent ubiquitination作为细胞死亡的检查点.
- 这一途径提供了一种替代机制来抑制亡.
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