线粒体酸酶PGAM5的功能位于多个死的死亡途径的融合点
Zhigao Wang1, Hui Jiang, She Chen
1Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Cell
|January 24, 2012
概括
编程性亡涉及RIP1和RIP3激酶. 线粒体酸酶PGAM5作为一个融合点,通过Drp1-介导的线粒体分裂来调节亡.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 编程性亡是一种细胞死亡形式,由RIP1和RIP3等特定激酶调节.
- TNF-α是编程性亡的关键诱导因子,涉及与MLKL的相互作用.
- 了解死细胞的上游调节者对于细胞死亡研究至关重要.
研究的目的:
- 为了确定参与TNF-α诱导的亡的蛋白质复合体.
- 阐明线粒体酸酶PGAM5在规划性亡中的作用.
- 将PGAM5定义为多重死亡途径的融合点.
主要方法:
- 蛋白质组分析以确定RIP1和RIP3复合体.
- 在PGAM5变体 (PGAM5L,PGAM5S),RIP3和MLKL的siRNA敲除中.
- 通过TNF-α,ROS和离子体诱导死亡的评估.
- 对Drp1招募,GTPase活性和在637.7血清下脱酸化的分析.
- 线粒体碎片化试验.
主要成果:
- 鉴定了RIP1和RIP3含有复合体,在死亡诱导后形成.
- PGAM5 (长短形式) 是这些复合体的一个组成部分.
- 通过各种刺激诱导的PGAM5减弱性缩的淘汰,而RIP3/MLKL淘汰只影响TNF-α诱导的缩.
- PGAM5S通过去酸化氨酸637来招募和激活Drp1,从而导致线粒体碎片化.
- 线粒体碎片化被确定为亡执行的早期步骤.
结论:
- PGAM5在编程性亡中起到关键的线粒体调节作用.
- PGAM5作为多个致死诱导途径的收点.
- 通过PGAM5介导的Drp1激活和随后的线粒体碎片化对于死亡是必不可少的.
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