PINK1 介导的 Parkin 泛素样结构域磷酸化使 Parkin 向线粒体易位并调节线粒体自噬。
PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy.
机构信息
Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
出版信息
Sci Rep. 2012;2:1002. doi: 10.1038/srep01002. Epub 2012 Dec 19.
Parkinson's disease genes PINK1 and parkin encode kinase and ubiquitin ligase, respectively. The gene products PINK1 and Parkin are implicated in mitochondrial autophagy, or mitophagy. Upon the loss of mitochondrial membrane potential (ΔΨm), cytosolic Parkin is recruited to the mitochondria by PINK1 through an uncharacterised mechanism - an initial step triggering sequential events in mitophagy. This study reports that Ser65 in the ubiquitin-like domain (Ubl) of Parkin is phosphorylated in a PINK1-dependent manner upon depolarisation of ΔΨm. The introduction of mutations at Ser65 suggests that phosphorylation of Ser65 is required not only for the efficient translocation of Parkin, but also for the degradation of mitochondrial proteins in mitophagy. Phosphorylation analysis of Parkin pathogenic mutants also suggests Ser65 phosphorylation is not sufficient for Parkin translocation. Our study partly uncovers the molecular mechanism underlying the PINK1-dependent mitochondrial translocation and activation of Parkin as an initial step of mitophagy.
帕金森病基因 PINK1 和 parkin 分别编码激酶和泛素连接酶。其产物 PINK1 和 Parkin 与线粒体自噬或 mitophagy 有关。在线粒体膜电位(ΔΨm)丧失后,PINK1 通过一种尚未确定的机制将细胞质中的 Parkin 募集到线粒体,这是触发 mitophagy 中连续事件的初始步骤。本研究报告称,在 ΔΨm 去极化时,Parkin 泛素样结构域(Ubl)中的 Ser65 可被 PINK1 依赖方式磷酸化。在 Ser65 引入突变表明,Ser65 的磷酸化不仅需要 Parkin 的有效易位,而且还需要 mitophagy 中线粒体蛋白的降解。对 Parkin 致病性突变体的磷酸化分析也表明,Ser65 磷酸化不足以促进 Parkin 的易位。我们的研究部分揭示了 PINK1 依赖性线粒体易位和 Parkin 激活的分子机制,这是 mitophagy 的初始步骤。