The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways
The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways
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DOI：
10.1016/j.cell.2011.11.030
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发表时间：
2012-01-20
期刊：
影响因子：
64.5
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
Wang, Zhigao;Jiang, Hui;Wang, Xiaodong
由TNF-α诱导的程序性坏死需要受体相互作用丝氨酸-苏氨酸激酶RIP 1和RIP 3的活性以及它们与混合谱系激酶结构域样蛋白MLKL的相互作用。我们报告的识别RIP 1和RIP 3的蛋白复合物，形成专门响应坏死诱导。这些复合物的一个组分是线粒体蛋白磷酸酶PGAM 5，其呈现为两种剪接变体，PGAM 5L（长形式）和PGAM 5S（短形式）。敲低任一种形式减弱了TNF-α以及活性氧（ROS）和钙离子载体诱导的坏死，而敲低RIP 3和MLKL仅阻断TNF-α介导的坏死。在坏死诱导后，PGAM 5S募集线粒体分裂因子Drp 1，并通过使Drp 1的丝氨酸637位点去磷酸化来激活其GTdR活性。drp 1激活导致线粒体断裂，这是坏死执行的早期和强制性步骤。这些数据将PGAM 5定义为多个坏死途径的汇聚点。
The programmed necrosis induced by TNF-alpha requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. One component of these complexes is the mitochondrial protein phosphatase PGAM5, which presents as two splice variants, PGAM5L (long form) and PGAM5S (short form). Knockdown of either form attenuated necrosis induced by TNF-a as well as reactive oxygen species (ROS) and calcium ionophore, whereas knockdown of RIP3 and MLKL blocked only TNF-alpha-mediated necrosis. Upon necrosis induction, PGAM5S recruited the mitochondrial fission factor Drp1 and activated its GTPase activity by dephosphorylating the serine 637 site of Drp1. Drp1 activation caused mitochondrial fragmentation, an early and obligatory step for necrosis execution. These data defined PGAM5 as the convergent point for multiple necrosis pathways.