揭示 NFE2L1 在应激反应和相关疾病中的作用,Redox Biology

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揭示 NFE2L1 在应激反应和相关疾病中的作用
Redox Biology ( IF 10.7 ) Pub Date : 2023-07-14 , DOI: 10.1016/j.redox.2023.102819
Xingzhu Liu ₁ , Chang Xu ₁ , Wanglong Xiao ₂ , Nianlong Yan ₃

Affiliation

核因子红细胞 2 (NF-E2) 相关因子 1 (NFE2L1，也称为 Nrf1) 是一种高度保守的转录因子，属于 CNC-bZIP 亚家族。它的重要性在于它对氧化还原平衡、蛋白酶体活性和器官完整性的控制。应激反应包括细胞和生物体用来应对由应激刺激引发的细胞外或细胞内应激的一系列补偿性适应。最近，大量证据表明，NFE2L1 在细胞应激适应中发挥着至关重要的作用：1）通过诱导抗氧化反应来应对氧化应激，2）通过调节泛素-蛋白酶体系统来解决蛋白毒性应激或内质网 (ER) 应激(UPS)、未折叠蛋白反应 (UPR) 和 ER 相关降解 (ERAD)。值得注意的是，NFE2L1 作为蛋白毒性应激适应的核心因子，在与蛋白酶体应激增强相关的癌症和神经退行性疾病中得到了广泛的研究。在这些情况下，利用 NFE2L1 抑制剂来减弱蛋白酶体“反弹”反应对于增强蛋白酶体抑制剂的功效具有巨大的潜力。此外，NFE2L1 的异常应激适应以及氧化还原和蛋白质稳态的紊乱会导致心血管疾病、炎症性疾病和自身免疫性疾病的病理生理并发症。因此，全面探索NFE2L1和NFE2L1介导的应激反应相关疾病的分子基础不仅有助于识别新的诊断和预后指标，而且有助于识别NFE2L1相关疾病的特异性治疗靶点。

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Unravelling the role of NFE2L1 in stress responses and related diseases

The nuclear factor erythroid 2 (NF-E2)-related factor 1 (NFE2L1, also known as Nrf1) is a highly conserved transcription factor that belongs to the CNC-bZIP subfamily. Its significance lies in its control over redox balance, proteasome activity, and organ integrity. Stress responses encompass a series of compensatory adaptations utilized by cells and organisms to cope with extracellular or intracellular stress initiated by stressful stimuli. Recently, extensive evidence has demonstrated that NFE2L1 plays a crucial role in cellular stress adaptation by 1) responding to oxidative stress through the induction of antioxidative responses, and 2) addressing proteotoxic stress or endoplasmic reticulum (ER) stress by regulating the ubiquitin-proteasome system (UPS), unfolded protein response (UPR), and ER-associated degradation (ERAD). It is worth noting that NFE2L1 serves as a core factor in proteotoxic stress adaptation, which has been extensively studied in cancer and neurodegeneration associated with enhanced proteasomal stress. In these contexts, utilization of NFE2L1 inhibitors to attenuate proteasome "bounce-back" response holds tremendous potential for enhancing the efficacy of proteasome inhibitors. Additionally, abnormal stress adaptations of NFE2L1 and disturbances in redox and protein homeostasis contribute to the pathophysiological complications of cardiovascular diseases, inflammatory diseases, and autoimmune diseases. Therefore, a comprehensive exploration of the molecular basis of NFE2L1 and NFE2L1-mediated diseases related to stress responses would not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for NFE2L1-related diseases.

更新日期：2023-07-14

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