Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate
Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate
复制标题
动态 PGAM5 多聚体使 BCL-xL 或 FUNDC1 去磷酸化以调节线粒体和细胞命运
DOI：
10.1038/s41418-019-0396-4
复制
发表时间：
2020-03-01
影响因子：
12.4
通讯作者：
Chen, Quan
中科院分区：
文献类型：
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作者：
Ma, Kaili;Zhang, Zhi;Chen, Quan
线粒体是高度动态的细胞器，并通过改变其分裂-融合周期、经历线粒体自噬或释放凋亡蛋白以启动细胞死亡来响应压力。感受不同压力和协调不同效应物的分子机制仍有待充分表征。在这里，我们表明，PGAM 5，它存在于二聚体和多聚体状态之间的平衡，去磷酸化BCL-xL抑制细胞凋亡或FUNDC 1激活线粒体分裂和线粒体自噬响应不同的压力。在长春碱处理的细胞中，PGAM 5使BCL-xL在Ser 62处去磷酸化以恢复BAX和巴克的BCL-xL隔离，从而抵抗细胞凋亡。亚硒酸盐诱导的氧化应激增加PGAM 5的多聚化，导致其从BCL-xL解离，这导致BCL-xL磷酸化和凋亡增加。一旦释放，更多的多聚体和活性PGAM 5去磷酸化FUNDC 1启动有丝分裂和线粒体自噬。由PGAM 5多聚化控制的PGAM 5与FUNDC 1和BCL-xL的相互作用充当有丝分裂/自噬和凋亡之间的分子开关。
Mitochondria are highly dynamic organelles and respond to stress by changing their fission-fusion cycle, undergoing mitophagy, or releasing apoptotic proteins to initiate cell death. The molecular mechanisms that sense different stresses and coordinate distinct effectors still await full characterization. Here, we show that PGAM5, which exists in an equilibrium between dimeric and multimeric states, dephosphorylates BCL-xL to inhibit apoptosis or FUNDC1 to activate mitofission and mitophagy in response to distinct stresses. In vinblastine-treated cells, PGAM5 dephosphorylates BCL-xL at Ser62 to restore BCL-xL sequestration of BAX and BAK and thereby resistance to apoptosis. Selenite-induced oxidative stress increases the multimerization of PGAM5, resulting in its dissociation from BCL-xL, which causes increased BCL-xL phosphorylation and apoptosis. Once freed, the more multimeric and active PGAM5 dephosphorylates FUNDC1 to initiate mitofission and mitophagy. The reciprocal interaction of PGAM5 with FUNDC1 and BCL-xL, controlled by PGAM5 multimerization, serves as a molecular switch between mitofission/mitophagy and apoptosis.