Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL
Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL
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DOI：
10.1074/jbc.ra118.006302
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发表时间：
2019-06-28
影响因子：
4.8
通讯作者：
Matsuda, Noriyuki
中科院分区：
文献类型：
--
作者：
Koyano, Fumika;Yamano, Koji;Matsuda, Noriyuki
PINK1 （PARK6）和PARKIN （PARK2）是隐性家族性帕金森病的致病基因。Parkin是一种泛素连接酶E3，它将泛素结合到受损的线粒体蛋白上以进行细胞器降解。PINK1是一种丝氨酸/苏氨酸激酶，仅在受损的线粒体上积累，磷酸化两个真正的底物，Parkin的泛素样结构域和泛素。我们和其他人已经发现Parkin的亚细胞定位和连接酶活性都是通过磷酸化泛素的相互作用来调节的。一旦PINK1定位于受损的线粒体，PINK1催化的磷泛素招募并激活Parkin。然后，Parkin向PINK1提供泛素链进行磷酸化。扩增的泛素作为一个信号，用于隔离和降解受损的线粒体。尽管已经报道了各种各样的Parkin底物，但对Parkin底物特异性的基础仍然知之甚少。此外，Parkin在线粒体上的初始活化和易位机制尚不清楚，因为受损线粒体上泛素的存在被认为是初始PINK1磷酸化过程的先决条件。在这里，我们发现人工线粒体靶向蛋白被Parkin泛素化，这表明Parkin的底物特异性不是由其氨基酸序列决定的。此外，随着线粒体E3、MITOL/March5的耗尽，Parkin的募集和激活被延迟。我们提出了一个模型，在这个模型中，Parkin募集和激活的最初步骤需要MITOL/March5蛋白泛素化，随后是pink1介导的磷酸化。由于PINK1和Parkin通过正反馈回路放大泛素信号，Parkin的低底物特异性可能促进了这一放大过程。
PINK1 (PARK6) and PARKIN (PARK2) are causal genes of recessive familial Parkinson's disease. Parkin is a ubiquitin ligase E3 that conjugates ubiquitin to impaired mitochondrial proteins for organelle degradation. PINK1, a Ser/Thr kinase that accumulates only on impaired mitochondria, phosphorylates two authentic substrates, the ubiquitin-like domain of Parkin and ubiquitin. Our group and others have revealed that both the subcellular localization and ligase activity of Parkin are regulated through interactions with phosphorylated ubiquitin. Once PINK1 localizes on impaired mitochondria, PINK1-catalyzed phosphoubiquitin recruits and activates Parkin. Parkin then supplies a ubiquitin chain to PINK1 for phosphorylation. The amplified ubiquitin functions as a signal for the sequestration and degradation of the damaged mitochondria. Although a bewildering variety of Parkin substrates have been reported, the basis for Parkin substrate specificity remains poorly understood. Moreover, the mechanism underlying initial activation and translocation of Parkin onto mitochondria remains unclear, because the presence of ubiquitin on impaired mitochondria is thought to be a prerequisite for the initial PINK1 phosphorylation process. Here, we show that artificial mitochondria-targeted proteins are ubiquitylated by Parkin, suggesting that substrate specificity of Parkin is not determined by its amino acid sequence. Moreover, recruitment and activation of Parkin are delayed following depletion of the mitochondrial E3, MITOL/March5. We propose a model in which the initial step in Parkin recruitment and activation requires protein ubiquitylation by MITOL/March5 with subsequent PINK1-mediated phosphorylation. Because PINK1 and Parkin amplify the ubiquitin signal via a positive feedback loop, the low substrate specificity of Parkin might facilitate this amplification process.