NRF2蛋白O-GlcNAc糖基化修饰在细胞氧化还原平衡中的功能及调控机制研究

O-GlcNAc是一种广泛存在于细胞浆和细胞核蛋白质丝/苏氨酸上的动态、可逆的翻译后修饰，与传统的糖基化不同而类似于磷酸化，在生命过程中发挥重要作用。近年来的研究表明，O-GlcNAc修饰参与了细胞氧化还原平衡的调控，然而其作为细胞氧化应激感应器的确切作用和分子机制还有待阐明。我们前期研究发现，调控细胞氧化还原内稳态的关键转录因子NRF2被O-GlcNAc修饰并确定了其修饰位点；进一步研究发现O-GlcNAc修饰能增强NRF2的稳定性和转录活性。该项目将深入阐明O-GlcNAc修饰对NRF2的调控作用及机制，并揭示O-GlcNAc修饰调控NRF2介导的细胞抗氧化作用和分子机制。该研究将为肿瘤、糖尿病、神经退行性疾病和慢性炎症等氧化应激相关疾病的预防和治疗提供新思路。

O-GlcNAc is an O-linked β-N-acetylglucosamine moiety attached to the side chain hydroxyl of a serine or threonine residue, which is found on numerous cytoplasm and nucleus proteins. O-GlcNAcylation is different from the classic glycosylation but similar to phosphorylation, which plays important roles in various physiological and pathological processes. Recent studies have shown that O-GlcNAcylation is not only a cellular metabolic sensor, but also involved in the regulation of cellular redox balance. However, the exact role and molecular mechanism of O-GlcNAc as a potential cellular oxidative stress sensor remains to be elucidated. Our previous study found that NRF2, a key transcription factor that regulates cellular redox homeostasis, is O-GlcNAcylated and identified its modification sites. Further studies showed that O-GlcNAcylation can enhance the stability and transcriptional activity of NRF2. This proposal will elucidate the regulatory effect of O-GlcNAc on NRF2, and reveal the roles and mechanisms of O-GlcNAcylation in NRF2-mediated cellular anti-oxidative activity. This research will provide new ideas for the treatment of diseases related to oxidative stress such as cancer, diabetes, neurodegenerative diseases and chronic inflammation.