Jeon Seo Jeong, Chung Kwang Chul
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
J Biol Chem. 2024 Apr;300(4):107198. doi: 10.1016/j.jbc.2024.107198. Epub 2024 Mar 18.
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 via 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.
了解调控功能关键蛋白稳定性的机制对于各种细胞过程、发育及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相关。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重要作用，其突变形式会导致早发性帕金森病。尽管其很重要，但调节PINK1蛋白稳定性的具体机制仍不清楚。本研究揭示了哺乳动物细胞中PINK1与含F盒和WD重复结构域7β（FBW7β）之间的细胞质相互作用。FBW7β是Skp1-Cullin-1-F盒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盒蛋白复合物和蛋白酶体途径调节PINK1的稳定性。它促进PINK1的K48连接的多聚泛素化，使其被标记降解。当缺乏FBW7时，PINK1会积累，导致羰基氰3-氯苯腙处理引发的线粒体自噬增强。此外，暴露于有毒化合物星形孢菌素会通过FBW7β加速PINK1的降解，这与细胞死亡增加相关。本研究揭示了控制PINK1蛋白稳定性的复杂机制，并阐明了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。
