Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Department of Physiology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Japan.
J Biol Chem. 2022 Jan;298(1):101448. doi: 10.1016/j.jbc.2021.101448. Epub 2021 Nov 24.
Nrf2 is an antioxidant transcriptional activator in many types of cells, and its dysfunction plays key roles in a variety of human disorders, including Parkinson's disease (PD). PD is characterized by the selective loss of dopaminergic neurons in PD-affected brain regions. Dopamine treatment of neuronal cells stimulates the production of reactive oxygen species (ROS) and increases ROS-dependent neuronal apoptosis. In this study, we found that the ubiquitin-specific protease 10 (USP10) protein reduces dopamine-induced ROS production of neuronal cells and ROS-dependent apoptosis by stimulating the antioxidant activity of Nrf2. USP10 interacted with the Nrf2 activator p62, increased the phosphorylation of p62, increased the interaction of p62 with the Nrf2 inhibitor Keap1, and stimulated Nrf2 antioxidant transcriptional activity. In addition, USP10 augmented dopamine-induced Nrf2 translation. Taken together, these results indicate that USP10 is a key regulator of Nrf2 antioxidant activity in neuronal cells and suggest that USP10 activators are promising therapeutic agents for oxidative stress-related diseases, including PD.
Nrf2 是许多类型细胞中的抗氧化转录激活因子，其功能障碍在包括帕金森病 (PD) 在内的多种人类疾病中发挥关键作用。PD 的特征是受影响大脑区域的多巴胺能神经元选择性丧失。多巴胺处理神经元细胞会刺激活性氧 (ROS) 的产生，并增加 ROS 依赖性神经元凋亡。在这项研究中，我们发现泛素特异性蛋白酶 10 (USP10) 蛋白通过刺激 Nrf2 的抗氧化活性，降低神经元细胞中多巴胺诱导的 ROS 产生和 ROS 依赖性凋亡。USP10 与 Nrf2 激活剂 p62 相互作用，增加了 p62 的磷酸化，增加了 p62 与 Nrf2 抑制剂 Keap1 的相互作用，并刺激了 Nrf2 抗氧化转录活性。此外，USP10 增强了多巴胺诱导的 Nrf2 翻译。总之，这些结果表明 USP10 是神经元细胞中 Nrf2 抗氧化活性的关键调节剂，并表明 USP10 激活剂是包括 PD 在内的与氧化应激相关疾病的有前途的治疗药物。
