Dodson Matthew, Zhang Donna D
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA, 85721.
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA, 85724.
Curr Pathobiol Rep. 2017 Jun;5(2):171-176. doi: 10.1007/s40139-017-0131-0. Epub 2017 Apr 19.
The goal of this review is to summarize the current knowledge in the field regarding the non-canonical activation of the NRF2 pathway. Specifically, we address what role p62 plays in mediating this pathway, which pathologies have been linked to the p62-dependent activation of NRF2, as well as what therapeutic strategies could be used to treat diseases associated with the non-canonical pathway.
It has recently been shown that autophagic dysfunction leads to the aggregation or autophagosomal accumulation of p62, which sequesters KEAP1, resulting in prolonged activation of NRF2. The ability of p62 to outcompete NRF2 for KEAP1 binding depends on its abundance, or post-translational modifications to its key domains. Furthermore, the relevance of the p62-dependent activation of NRF2 in disease has been demonstrated in human hepatocellular carcinomas, as well as neurodegenerative diseases.
These findings indicate that targeting p62, or the enzymes that modify it, could prove to be an advantageous strategy for treating diseases associated with autophagy dysregulation and prolonged activation of NRF2. Other therapeutic possibilities include restoring proper autophagic function, or directly inhibiting NRF2 or its targets, to restore redox and metabolic homeostasis. Future studies will help further clarify the mechanisms, regulation, and relevance of the non-canonical pathway in driving disease pathogenesis.
本综述的目的是总结该领域目前关于NRF2途径非经典激活的知识。具体而言，我们探讨p62在介导该途径中所起的作用、哪些病理状态与p62依赖的NRF2激活相关联，以及可用于治疗与非经典途径相关疾病的治疗策略。
最近研究表明，自噬功能障碍会导致p62聚集或自噬体积累，从而隔离KEAP1，导致NRF2持续激活。p62在与KEAP1结合方面胜过NRF2的能力取决于其丰度或对其关键结构域的翻译后修饰。此外，NRF2的p62依赖激活在疾病中的相关性已在人类肝细胞癌以及神经退行性疾病中得到证实。
这些发现表明，靶向p62或修饰它的酶可能是治疗与自噬失调和NRF2持续激活相关疾病的有利策略。其他治疗可能性包括恢复适当的自噬功能，或直接抑制NRF2或其靶点，以恢复氧化还原和代谢稳态。未来的研究将有助于进一步阐明非经典途径在驱动疾病发病机制中的机制、调节和相关性。
