A Regulatory Signaling Loop Comprising the PGAM5 Phosphatase and CK2 Controls Receptor-Mediated Mitophagy
A Regulatory Signaling Loop Comprising the PGAM5 Phosphatase and CK2 Controls Receptor-Mediated Mitophagy
复制标题
包含 PGAM5 磷酸酶和 CK2 的调节信号环路控制受体介导的线粒体自噬
DOI：
10.1016/j.molcel.2014.02.034
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发表时间：
2014-05-08
期刊：
影响因子：
16
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Chen, Guo;Han, Zhe;Chen, Quan
线粒体自噬（mitochondrialautophagy）是通过选择性地去除受损或不需要的线粒体来控制线粒体质量的主要机制。LC 3和线粒体自噬受体之间的相互作用，如FUNDC 1，其中含有一个LC 3相互作用区（LIR），是必不可少的选择性过程。然而，线粒体压力如何感应到激活受体介导的线粒体自噬仍然不清楚。在这里，我们确定，脑内定位的PGAM 5磷酸酶与FUNDC 1在丝氨酸13（Ser-13）缺氧或羰基氰化物对三氟甲氧基苯腙（FCCP）治疗后，去磷酸化。由PGAM 5催化的FUNDC 1的去磷酸化增强了其与LC 3的相互作用，这在PGAM 5敲低或引入包含FUNDC 1的Ser-13和LIR的细胞可渗透的未磷酸化肽后被废除。我们进一步观察到CK 2磷酸化FUNDC 1以逆转PGAM 5在线粒体自噬激活中的作用。我们的研究结果揭示了一个机制的信号通路，连接到FUNDC 1的PGAM 5，最终诱导线粒体自噬的去磷酸化的损伤信号。
Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy.