Tao Shasha, Liu Pengfei, Luo Gang, Rojo de la Vega Montserrat, Chen Heping, Wu Tongde, Tillotson Joseph, Chapman Eli, Zhang Donna D
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA
Mol Cell Biol. 2017 Mar 31;37(8). doi: 10.1128/MCB.00660-16. Print 2017 Apr 15.
Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.
应激反应转录因子NRF2的激活是对抗氧化或亲电损伤的主要防御线。在基础条件下，NRF2被KEAP1-CUL3-RBX1 E3泛素连接酶复合物持续泛素化，并被靶向蛋白酶体进行降解（经典机制）。然而，从CUL3复合物到最终蛋白酶体降解的途径此前尚不清楚。p97是一种靶向泛素的ATP依赖性分离酶，可从膜、蛋白质复合物或染色质中提取泛素化的客户蛋白，在自噬和泛素蛋白酶体系统（UPS）中起重要作用。在本研究中，我们表明，p97通过经典途径负向调节NRF2，在异二聚体辅助因子UFD1/NPL4和含UBA-UBX的蛋白UBXN7的帮助下，从KEAP1-CUL3 E3复合物中提取泛素化的NRF2，以实现高效的蛋白酶体降解。鉴于NRF2在化疗耐药中的作用以及对用于治疗癌症的p97抑制剂的兴趣激增，我们的结果表明，双重p97/NRF2抑制剂可能提供一种更有效且长期的p97靶向治疗途径。
