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Critical role of mitochondrial ubiquitination and the OPTN–ATG9A axis in mitophagy
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2020-06-17 , DOI: 10.1083/jcb.201912144
Koji Yamano 1 , Reika Kikuchi 1 , Waka Kojima 1, 2, 3 , Ryota Hayashida 1, 2, 3 , Fumika Koyano 1 , Junko Kawawaki 1 , Takuji Shoda 4 , Yosuke Demizu 4 , Mikihiko Naito 5 , Keiji Tanaka 3 , Noriyuki Matsuda 1
Affiliation  

Damaged mitochondria are selectively eliminated in a process called mitophagy. Parkin and PINK1, proteins mutated in Parkinson’s disease, amplify ubiquitin signals on damaged mitochondria with the subsequent activation of autophagic machinery. Autophagy adaptors are thought to link ubiquitinated mitochondria and autophagy through ATG8 protein binding. Here, we establish methods for inducing mitophagy by mitochondria-targeted ubiquitin chains and chemical-induced mitochondrial ubiquitination. Using these tools, we reveal that the ubiquitin signal is sufficient for mitophagy and that PINK1 and Parkin are unnecessary for autophagy activation per se. Furthermore, using phase-separated fluorescent foci, we show that the critical autophagy adaptor OPTN forms a complex with ATG9A vesicles. Disruption of OPTN–ATG9A interactions does not induce mitophagy. Therefore, in addition to binding ATG8 proteins, the critical autophagy adaptors also bind the autophagy core units that contribute to the formation of multivalent interactions in the de novo synthesis of autophagosomal membranes near ubiquitinated mitochondria.

中文翻译:


线粒体泛素化​​和 OPTN-ATG9A 轴在线粒体自噬中的关键作用



受损的线粒体在称为线粒体自噬的过程中被选择性消除。 Parkin 和 PINK1 是帕金森病中突变的蛋白质,可放大受损线粒体上的泛素信号,随后激活自噬机制。自噬接头被认为通过 ATG8 蛋白结合将泛素化线粒体和自噬连接起来。在这里,我们建立了通过线粒体靶向泛素链和化学诱导的线粒体泛素化​​诱导线粒体自噬的方法。使用这些工具,我们揭示了泛素信号对于线粒体自噬来说是足够的,而 PINK1 和 Parkin 对于自噬激活本身来说是不必要的。此外,使用相分离荧光焦点,我们表明关键的自噬接头 OPTN 与 ATG9A 囊泡形成复合物。 OPTN-ATG9A 相互作用的破坏不会诱导线粒体自噬。因此,除了结合 ATG8 蛋白外,关键的自噬接头还结合自噬核心单元,这些单元有助于在泛素化线粒体附近的自噬体膜从头合成中形成多价相互作用。
更新日期:2020-06-17
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