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首页> 外文期刊>EMBO reports >(Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation
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(Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation

机译：PINK1依赖性泛素磷酸化的（病理）生理相关性

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摘要

Mutations in PINK1 and PARKIN cause recessive, early-onset Parkinson's disease (PD). Together, these two proteins orchestrate a protective mitophagic response that ensures the safe disposal of damaged mitochondria. The kinase PINK1 phosphorylates ubiquitin (Ub) at the conserved residue S65, in addition to modifying the E3 ubiquitin ligase Parkin. The structural and functional consequences of Ub phosphorylation (pS65-Ub) have already been suggested from invitro experiments, but its (patho-)physiological significance remains unknown. We have generated novel antibodies and assessed pS65-Ub signals invitro and in cells, including primary neurons, under endogenous conditions. pS65-Ub is dependent on PINK1 kinase activity as confirmed in patient fibroblasts and postmortem brain samples harboring pathogenic mutations. We show that pS65-Ub is reversible and barely detectable under basal conditions, but rapidly induced upon mitochondrial stress in cells and amplified in the presence of functional Parkin. pS65-Ub accumulates in human brain during aging and disease in the form of cytoplasmic granules that partially overlap with mitochondrial, lysosomal, and total Ub markers. Additional studies are now warranted to further elucidate pS65-Ub functions and fully explore its potential for biomarker or therapeutic development.
机译：PINK1和PARKIN的突变会引起隐性，早发性帕金森氏病（PD）。这两种蛋白质共同构成了一种保护性的线粒体反应，可确保安全处理受损的线粒体。激酶PINK1除了修饰E3泛素连接酶Parkin外，还在保守残基S65处使泛素（Ub）磷酸化。 Ub磷酸化（pS65-Ub）的结构和功能后果已从体外实验中提出，但其（病理）生理学意义仍然未知。我们已经产生了新型抗体，并在内源性条件下体外和在细胞（包括原代神经元）中评估了pS65-Ub信号。 pS65-Ub依赖于PINK1激酶活性，这在患者成纤维细胞和具有致病突变的死后脑样本中已得到证实。我们显示，pS65-Ub在基础条件下是可逆的，几乎无法检测到，但在细胞中发生线粒体应激时迅速诱导，并在功能性Parkin存在下扩增。 pS65-Ub在衰老和疾病期间以细胞质颗粒的形式在人脑中积累，该颗粒与线粒体，溶酶体和总Ub标记物部分重叠。现在有必要进行更多的研究，以进一步阐明pS65-Ub的功能，并充分探索其在生物标志物或治疗开发中的潜力。

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