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首页> 外文期刊>日本磁気共鳴医学会雑誌 >Quantitative Proteomics Reveal a Feedforward Mechanism for Mitochondrial PARKIN Translocation and Ubiquitin Chain Synthesis
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Quantitative Proteomics Reveal a Feedforward Mechanism for Mitochondrial PARKIN Translocation and Ubiquitin Chain Synthesis

机译：定量蛋白质组学揭示了线粒体PARKIN易位和泛素链合成的前馈机制

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摘要

Phosphorylation is often used to promote protein ubiquitylation, yet we rarely understand quantitatively how ligase activation and ubiquitin (UB) chain assembly are integrated with phosphoregulation. Here we employ quantitative proteomics and live-cell imaging to dissect individual steps in the PINK1 kinase-PARKIN UB ligase mitochondrial control pathway disrupted in Parkinson's disease. PINK1 plays a dual role by phosphorylating PARKIN on its UB-like domain and poly-UB chains on mitochondria. PARKIN activation by PINK1 produces canonical and noncanonical UB chains on mitochondria, and PARKIN-dependent chain assembly is required for accumulation of poly-phospho-UB (poly-p-UB) on mitochondria. In vitro, PINK1 directly activates PARKIN'S ability to assemble canonical and noncanonical UB chains and promotes association of PARKIN with both p-UB and poly-p-UB. Our data reveal a feedforward mechanism that explains how PINK1 phosphorylation of both PARKIN and poly-UB chains synthesized by PARKIN drives a program of PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage.
机译：磷酸化通常用于促进蛋白质泛素化，但是我们很少定量地了解连接酶激活和泛素（UB）链组装如何与磷酸化结合。在这里，我们采用定量蛋白质组学和活细胞成像技术来剖析PINK1激酶-PARKIN UB连接酶线粒体控制途径在帕金森氏病中受到破坏的各个步骤。 PINK1通过在其UB样域和线粒体上的多UB链上磷酸化PARKIN发挥双重作用。 PINK1激活PARKIN会在线粒体上产生规范性和非规范性UB链，而依赖于PARKIN的链组装对于线粒体上聚磷酸UB（poly-p-UB）的积累是必需的。在体外，PINK1直接激活PARKIN组装规范和非规范UB链的能力，并促进PARKIN与p-UB和poly-p-UB缔合。我们的数据揭示了一种前馈机制，该机制解释了PARKIN和由PARKIN合成的poly-UB链的PINK1磷酸化如何驱动PARKIN募集和线粒体泛素化​​以响应线粒体损伤的程序。

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