Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy
Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy
复制标题
DOI：
10.15252/embj.201798899
复制
发表时间：
2018-11-02
期刊：
影响因子：
11.4
通讯作者：
Tagaya, Mitsuo
中科院分区：
文献类型：
--
作者：
Sugo, Masashi;Kimura, Hana;Tagaya, Mitsuo
PGAM5是一种线粒体蛋白磷酸酶，在遗传和生化上与PINK1相关，通过使线粒体裂变因子Drp1去磷酸化来促进线粒体分裂。在线粒体自噬开始时，PGAM5被PARL切割，PARL是一种在健康细胞中降解PINK1的菱形蛋白酶，切割形式通过使线粒体自噬受体FUNDC1去磷酸化，促进自噬体吞噬受损的线粒体。在这里，我们发现PGAM5的功能和定位受syntaxin 17 （Stx17）的调控，syntaxin 17是一种线粒体相关的膜/线粒体蛋白，参与喂养细胞的线粒体动力学和饥饿细胞的自噬。在健康细胞中，Stx17的缺失导致PGAM5在线粒体内聚集，从而导致Drp1去磷酸化失败，导致线粒体伸长。在帕金森介导的线粒体自噬中，Stx17是PGAM5与FUNDC1相互作用的先决条件。我们的研究结果表明，Stx17-PGAM5轴在线粒体分裂和PINK1/帕金森介导的线粒体自噬中起关键作用。
PGAM5, a mitochondrial protein phosphatase that is genetically and biochemically linked to PINK1, facilitates mitochondrial division by dephosphorylating the mitochondrial fission factor Drp1. At the onset of mitophagy, PGAM5 is cleaved by PARL, a rhomboid protease that degrades PINK1 in healthy cells, and the cleaved form facilitates the engulfment of damaged mitochondria by autophagosomes by dephosphorylating the mitophagy receptor FUNDC1. Here, we show that the function and localization of PGAM5 are regulated by syntaxin 17 (Stx17), a mitochondria-associated membrane/mitochondria protein implicated in mitochondrial dynamics in fed cells and autophagy in starved cells. In healthy cells, loss of Stx17 causes PGAM5 aggregation within mitochondria and thereby failure of the dephosphorylation of Drp1, leading to mitochondrial elongation. In Parkin-mediated mitophagy, Stx17 is prerequisite for PGAM5 to interact with FUNDC1. Our results reveal that the Stx17-PGAM5 axis plays pivotal roles in mitochondrial division and PINK1/Parkin-mediated mitophagy.