KEAP1型
自噬
细胞生物学
串扰
袋3
磷酸化
生物
泛素
细胞质
转录因子
信号转导
化学
生物化学
细胞凋亡
基因
光学
物理
作者
Weiwei Zhang,Feng Cong,Hong Jiang
标识
DOI:10.1016/j.arr.2020.101207
摘要
In mammals, the Keap1-Nrf2-ARE pathway (henceforth, “the Nrf2 pathway”) and autophagy are major intracellular defence systems that combat oxidative damage and maintain homeostasis. p62/SQSTM1, a ubiquitin-binding autophagy receptor protein, links the Nrf2 pathway and autophagy. Phosphorylation of p62 dramatically enhances its affinity for Keap1, which induces Keap1 to release Nrf2, and the p62-Keap1 heterodimer recruits LC3 and mediates the permanent degradation of Keap1 in the selective autophagy pathway. Eventually, Nrf2 accumulates in the cytoplasm and then translocates into the nucleus to activate the transcription of downstream genes that encode antioxidant enzymes, which protect cells from oxidative damage. Since Nrf2 also upregulates the expression of the p62 gene, a p62-Keap1-Nrf2 positive feedback loop is created that further enhances the protective effect on cells. Studies have shown that the p62-activated noncanonical Nrf2 pathway is an important marker of neurodegenerative diseases. The p62-Keap1-Nrf2 positive feedback loop and the Nrf2 pathway are involved in eliminating the ROS and protein aggregates induced by AD. Therefore, maintaining the homeostasis of the p62-Keap1-Nrf2 positive feedback loop, which is a bridge between the Nrf2 pathway and autophagy, may be a potential target for the treatment of AD.
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