PDF(Pubmed)
Abstract：
Ubiquitination of mitochondrial proteins provides a basis for the downstream recruitment of mitophagy machinery, yet whether ubiquitination of the machinery itself contributes to mitophagy is unknown. Here, we show that K63-linked polyubiquitination of the key mitophagy regulator TBK1 is essential for its mitophagy functions. This modification is catalyzed by the ubiquitin ligase TRIM5α. Mitochondrial damage triggers TRIM5α\'s auto-ubiquitination and its interaction with ubiquitin-binding autophagy adaptors including NDP52, optineurin, and NBR1. Autophagy adaptors, along with TRIM27, enable TRIM5α to engage with TBK1. TRIM5α with intact ubiquitination function is required for the proper accumulation of active TBK1 on damaged mitochondria in Parkin-dependent and Parkin-independent mitophagy pathways. Additionally, we show that TRIM5α can directly recruit autophagy initiation machinery to damaged mitochondria. Our data support a model in which TRIM5α provides a self-amplifying, mitochondria-localized, ubiquitin-based, assembly platform for TBK1 and mitophagy adaptors that is ultimately required to recruit the core autophagy machinery.
摘要：
线粒体蛋白质的泛素化为线粒体自噬机制的下游募集提供了基础，然而，机器本身的泛素化是否有助于线粒体自噬尚不清楚。这里,我们表明，关键的线粒体自噬调节因子TBK1的K63连接的聚泛素化对其线粒体自噬功能至关重要。这种修饰由泛素连接酶TRIM5α催化。线粒体损伤触发TRIM5α的自动泛素化及其与泛素结合自噬衔接子的相互作用，包括NDP52，视神经磷酸酶，和NBR1。自噬适配器,与TRIM27一起，使TRIM5α与TBK1接合。具有完整泛素化功能的TRIM5α对于在Parkin依赖性和Parkin非依赖性线粒体自噬途径中受损线粒体上的活性TBK1的适当积累是必需的。此外,我们表明TRIM5α可以直接招募受损线粒体的自噬启动机制。我们的数据支持一个模型，其中TRIM5α提供了自放大功能，线粒体定位，泛素为基础，TBK1和线粒体自噬适配器的组装平台，最终需要招募核心自噬机制。
