核因子E2相关因子1诸多亚型的产生机制及其在疾病中的作用

The Mechanisms of the Production of Different Isoforms of Nuclear Factor E2-related Factor 1 and Their Role in Diseases

核因子E2相关因子1(nuclear factor-erythroid 2 related factor 1,Nrf1/Nfe2l1)在个体正常生长发育过程中具有维持细胞内稳态和器官完整性的作用。其功能缺失会产生严重的氧化应激和基因组不稳定等,继而导致肝癌、神经退行性疾病等多种疾病。近年研究发现,Nrf1存在多种具有不同程度活化活性甚至相反活性的亚型,这些亚型的分布可能在肿瘤的发生发展过程中具有重要作用。为了更好地了解Nrf1在组织细胞中所发挥的功能,本文简要介绍Nrf1的发现历程,并从选择性剪切加工、内部选择性翻译起始、翻译后剪切加工等方面阐述Nrf1亚型的产生机制,同时详细阐明“跨膜动态加工”、“位点特异性剪切加工”、“泛素依赖性剪切加工”3种翻译后加工模型的差异。最后,介绍Nrf1各亚型的生物学功能及其产生过程出现异常时在疾病中的作用。本文着重对Nrf1各亚型产生机制及其在疾病中的作用进行综述,力求为寻找肿瘤治疗的新策略提供新的方向。

During the normal process of biological growth and development,NF-E2-related factor 1(Nrf1/Nfe2l1)plays a unique role in maintaining intracellular homeostasis and organ integrity.The deficiency of Nrf1 will lead to severe oxidative stress,genomic instability,and result in liver cancer,neurodegenerative disorder and other diseases.In recent years,it has been found that Nrf1 could yield different activated isoforms or even opposite activity isoforms in a variety of ways to perform distinct functions,and the distribution of these isoforms may play a vital role in the process of tumor development.Therefore,to gain a better understanding of the function of Nrf1 isoforms in cells and tissues,we first briefly introduced its discovery process,and demonstrated the multiple mechanisms of distinct isoform production including selective shear processing,internal selective translation initiation,and post-translation shear processing.More importantly,three different post-translational processing models,transmembrane dynamic processing,site-specific processing,ubiquitin-dependent processing,were expounded in detail.Furthermore,the biological function of different isoforms of Nrf1 and its role in diseases were also summarized in the last section.Collectively,we focus on the production mechanism of different isoforms of Nrf1 and their roles in diseases so as to lay a foundation for finding new strategies for tumor treatment.