FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provides a target for Pink1 phosphorylation in vivo
FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provides a target for Pink1 phosphorylation in vivo
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FBXO7/ntc 和 USP30 拮抗地设定基础线粒体自噬的泛素化阈值，并为 Pink1 体内磷酸化提供靶点
DOI：
10.1101/2022.10.10.511602
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Sanchez-Martinez A
中科院分区：
文献类型：
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作者：
Sanchez-Martinez A
对帕金森病（PD）遗传性相关基因的功能分析揭示了对致病机制的生物过程的基本见解。 PARK15/FBXO7 突变导致常染色体隐性 PD，FBXO7 已被证明可以调节线粒体稳态。我们研究了 FBXO7 及其果蝇直系同源物 ntc 共享功能同源性的程度，并探讨了其在体内线粒体自噬中的作用。我们表明ntc突变体部分表型Pink1和parkin突变体和ntcover表达抑制parkin表型。此外，ntc 可以通过促进线粒体蛋白的泛素化，以独立于 Pink1 和 Parkin 的方式调节基础线粒体自噬，而去泛素化酶 USP30 则相反。这种基础泛素化作为 Pink1 介导的磷酸化的底物，触发应激诱导的线粒体自噬。我们建议 FBXO7/ntc 与 USP30 平衡工作，为体内基础条件下的线粒体质量控制提供检查点，并为治疗方法提供新途径。
Functional analyses of genes linked to heritable forms of Parkinson’s disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations inPARK15/FBXO7cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and itsDrosophilaorthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show thatntcmutants partially phenocopyPink1andparkinmutants andntcoverexpression supressesparkinphenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.