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A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy

机译:包含PGAM5磷酸酶和CK2的调节信号回路控制受体介导的线粒体吞噬

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摘要

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.
机译:线粒体自噬或线粒体吞噬是通过选择性去除受损或不需要的线粒体而参与线粒体质量控制的主要机制。 LC3和线粒体受体(例如带有LC3相互作用区域(LIR)的FUNDC1)之间的相互作用对于此选择性过程至关重要。但是,如何感知线粒体应激以激活受体介导的线粒体的作用仍然不清楚。在这里,我们确定低氧或羰基氰化物对三氟甲氧基苯基hypo(FCCP)处理后,线粒体定位的PGAM5磷酸酶与丝氨酸13(Ser-13)上的FUNDC1相互作用并使其去磷酸化。 PGAM5催化的FUNDC1的去磷酸化增强了它与LC3的相互作用,在敲除PGAM5或引入包含FUNDC1的Ser-13和LIR的可渗透细胞的非磷酸化肽后,LC3的相互作用被取消。我们进一步观察到,CK2使FUNDC1磷酸化,以逆转PGAM5在线粒体激活中的作用。我们的结果揭示了一种机械信号通路,该通路将线粒体破坏信号连接到PGAM5对FUNDC1的去磷酸化作用,最终导致线粒体吞噬。

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