选择性自噬接头蛋白p62与Keap1-Nrf2信号通路在神经退行性疾病中的研究进展

Research advances in the role of the selective autophagy adaptor protein p62 and the Keap1-Nrf2 signaling pathway in neurodegenerative diseases

摘要:

在自噬小体形成的过程中，选择性自噬接头蛋白p62作为连接自噬相关蛋白、LC3、聚泛素化蛋白之间的桥梁，通过泛素信号途径将受损的蛋白质、线粒体及入侵的细菌转运到自噬小体中并降解。p62作为一种自噬衔接蛋白将自噬和Keap1-Nrf2 通路相关联。p62可竞争性结合Keap1，通过自噬途径将其清除，促使Nrf2解离入核，Nrf2结合到下游抗氧化元件p62启动子区又可促进p62的生成，形成正性反馈环路。神经退行性疾病病因复杂、发病机制尚不清楚，自噬失调以p62调控的非经典途径激活Keap1-Nrf2信号通路成为该领域研究热点。

Abstract:

During the formation of autophagosomes, the selective autophagy adaptor protein p62 acts as the bridge between autophagy-related proteins, LC3, and polyubiquitinated proteins and transports damaged proteins, mitochondria, and invading bacteria to autophagosomes for degradation through the ubiquitin signaling pathways. As an autophagy adaptor protein, p62 associates autophagy with the Keap1-Nrf2 signaling pathway and can competitively bind to Keap1 and then clear it via the autophagy pathway. In addition, p62 promotes the dissociation and nuclear import of Nrf2, which, in turn, promotes the generation of p62 by binding to the downstream antioxidant response element on its promotor region, forming a positive feedback loop. Neurodegenerative diseases have complex etiologies and unclear pathogeneses, and autophagy dysregulation activating the Keap1-Nrf2 signaling pathway through the p62-regulated non-classical pathway has become a research hotspot in this field.