Understanding the mechanisms that govern the stability of functionally crucial proteins is essential for various cellular processes, development, and overall cell viability. Disturbances in protein homeostasis are linked to the pathogenesis of neurodegenerative diseases. PTEN-induced kinase 1 (PINK1), a protein kinase, plays a significant role in mitochondrial quality control and cellular stress response, and its mutated forms lead to early-onset Parkinson's disease. Despite its importance, the specific mechanisms regulating PINK1 protein stability have remained unclear. This study reveals a cytoplasmic interaction between PINK1 and F-box and WD repeat domain–containing 7β (FBW7β) in mammalian cells. FBW7β, a component of the Skp1-Cullin-1-F-box protein complex–type ubiquitin ligase, is instrumental in recognizing substrates. Our findings demonstrate that FBW7β regulates PINK1 stability through the Skp1-Cullin-1-F-box protein complex and the proteasome pathway. It facilitates the K48-linked polyubiquitination of PINK1, marking it for degradation. When FBW7 is absent, PINK1 accumulates, leading to heightened mitophagy triggered by carbonyl cyanide 3-chlorophenylhydrazone treatment. Moreover, exposure to the toxic compound staurosporine accelerates PINK1 degradation FBW7β, correlating with increased cell death. This study unravels the intricate mechanisms controlling PINK1 protein stability and sheds light on the novel role of FBW7β. These findings deepen our understanding of PINK1-related pathologies and potentially pave the way for therapeutic interventions.

中文翻译：

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SCF-FBW7β E3 连接酶介导丝氨酸/苏氨酸蛋白激酶 PINK1 的泛素化和降解

了解控制功能关键蛋白稳定性的机制对于各种细胞过程、发育和整体细胞活力至关重要。蛋白质稳态的紊乱与神经退行性疾病的发病机制有关。 PTEN 诱导激酶 1 (PINK1) 是一种蛋白激酶，在线粒体质量控制和细胞应激反应中发挥着重要作用，其突变形式会导致早发性帕金森病。尽管它很重要，但调节 PINK1 蛋白稳定性的具体机制仍不清楚。这项研究揭示了哺乳动物细胞中 PINK1 和 F-box 以及包含 WD 重复结构域的 7β (FBW7β) 之间的细胞质相互作用。 FBW7β 是 Skp1-Cullin-1-F-box 蛋白复合物型泛素连接酶的一个组成部分，有助于识别底物。我们的研究结果表明，FBW7β 通过 Skp1-Cullin-1-F-box 蛋白复合物和蛋白酶体途径调节 PINK1 稳定性。它促进 PINK1 的 K48 连接多泛素化，标记其降解。当 FBW7 缺失时，PINK1 会积累，导致羰基氰化物 3-氯苯腙处理引发的线粒体自噬增强。此外，接触有毒化合物星形孢菌素会加速 PINK1 降解 FBW7β，与细胞死亡增加相关。这项研究揭示了控制 PINK1 蛋白稳定性的复杂机制，并揭示了 FBW7β 的新作用。这些发现加深了我们对 PINK1 相关病理学的理解，并可能为治疗干预铺平道路。