Xu Meng, Li Wanzhen, Xu Ruihong, Liu Lixia, Wu Zhihan, Li Wenzhe, Ma Chao, Xue Lei
Department of Nuclear Medicine, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, Shanghai, China.
Department of Nuclear Medicine, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 10th People's Hospital, 200072, Shanghai, China.
Redox Biol. 2025 Apr;81:103537. doi: 10.1016/j.redox.2025.103537. Epub 2025 Feb 8.
Reactive oxygen species (ROS) play a pivotal role in maintaining tissue homeostasis, yet their overabundance can impair normal cellular functions, induce cell death, and potentially lead to neurodegenerative disorders. This study identifies Drosophila Glycoprotein 93 (Gp93) as a crucial factor that safeguards tissue homeostasis and preserves normal neuronal functions by preventing ROS-induced, JNK-dependent apoptotic cell death. Firstly, loss of Gp93 induces JNK-dependent apoptosis primarily through the induction of ROS. Secondary, neuro-specific depletion of Gp93 results in ROS-JNK-mediated neurodegeneration. Thirdly, overexpression of Gp93 effectively curtails oxidative stress and neurodegeneration caused by paraquat exposure or the aging process. Furthermore, these functions of Gp93 can be substituted by its human ortholog, HSP90B1. Lastly, depletion of HSP90B1 in cultured human cells triggers ROS production, JNK activation, and apoptosis. Thus, this study not only unveils a novel physiological function of Gp93, but also provides valuable insights for understanding the physiological and pathological functions of human HSP90B1.
活性氧（ROS）在维持组织内环境稳定中起关键作用，然而其过量会损害正常细胞功能、诱导细胞死亡，并可能导致神经退行性疾病。本研究确定果蝇糖蛋白93（Gp93）是一个关键因素，它通过防止ROS诱导的、JNK依赖的凋亡性细胞死亡来维护组织内环境稳定并保持正常神经元功能。首先，Gp93的缺失主要通过诱导ROS来诱导JNK依赖的凋亡。其次，Gp93的神经特异性缺失导致ROS-JNK介导的神经退行性变。第三，Gp93的过表达有效减少了百草枯暴露或衰老过程引起的氧化应激和神经退行性变。此外，Gp93的这些功能可被其人类同源物HSP90B1替代。最后，在培养的人类细胞中HSP90B1的缺失会触发ROS产生、JNK激活和凋亡。因此，本研究不仅揭示了Gp93的一种新的生理功能，也为理解人类HSP90B1的生理和病理功能提供了有价值的见解。
