除了在核糖体生物发生中的典型功能,最近在核仁在应激反应中的迷人作用方面取得了重大进展,细胞命运决定和疾病进展。核仁应力,一个新兴的概念,描述了由于应激条件下rRNA合成和核糖体生物发生受损而导致的异常核仁结构和功能,与各种信号转导有关,包括但不限于Mdm2-p53、NF-κB和HIF-1α途径。研究发现,当细胞遇到各种压力条件时,核仁是应力传感器和信号中枢,比如营养剥夺,DNA损伤与氧化和热应激。因此,核仁应激在细胞命运的决定中起着举足轻重的作用,如细胞凋亡,衰老,自噬和分化,响应应力引起的损伤。核仁稳态已参与各种慢性疾病的发病机制,特别是肿瘤发生,神经退行性疾病和代谢紊乱。机制见解揭示了核仁启动的信号传导在这些疾病的进展中不可或缺的作用。因此,核仁应激的干预可能为开发针对这些疾病的新疗法铺平道路。在这次审查中,我们系统地总结了将核仁与应激反应联系起来的最新发现,信号转导和细胞命运决定,聚焦于核仁压力驱动疾病进展的机制,并强调了介入核仁在疾病治疗中的优点。
Besides the canonical function in ribosome biogenesis, there have been significant recent advances towards the fascinating roles of the
nucleolus in stress response, cell destiny decision and disease progression. Nucleolar stress, an emerging concept describing aberrant nucleolar structure and function as a result of impaired rRNA synthesis and ribosome biogenesis under stress conditions, has been linked to a variety of signaling transductions, including but not limited to Mdm2-p53, NF-κB and HIF-1α pathways. Studies have uncovered that
nucleolus is a stress sensor and signaling hub when cells encounter various stress conditions, such as nutrient deprivation, DNA damage and oxidative and thermal stress. Consequently, nucleolar stress plays a pivotal role in the determination of cell fate, such as apoptosis, senescence, autophagy and differentiation, in response to stress-induced damage. Nucleolar homeostasis has been involved in the pathogenesis of various chronic diseases, particularly tumorigenesis, neurodegenerative diseases and metabolic disorders. Mechanistic insights have revealed the indispensable role of
nucleolus-initiated signaling in the progression of these diseases. Accordingly, the intervention of nucleolar stress may pave the path for developing novel therapies against these diseases. In this review, we systemically summarize recent findings linking the
nucleolus to stress responses, signaling transduction and cell-fate decision, set the spotlight on the mechanisms by which nucleolar stress drives disease progression, and highlight the merit of the intervening
nucleolus in disease treatment.