Hayes John D, Dayalan Naidu Sharadha, Dinkova-Kostova Albena T
Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
Trends Biochem Sci. 2025 Mar;50(3):179-205. doi: 10.1016/j.tibs.2024.12.010. Epub 2025 Jan 27.
Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3, CRL4, SCF, and Hrd1). CRL3 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCF requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3 to alleviate stress and restore homeostasis.
转录因子NF-E2 p45相关因子2（Nrf2）协调机体对抗氧化剂和硫醇反应性亲电试剂的防御机制。它在蛋白质稳定性水平上受到多种E3泛素连接酶（CRL3、CRL4、SCF和Hrd1）的调控。CRL3最为重要，因为在稳态条件下它会持续将Nrf2靶向蛋白酶体降解，但氧化应激源可阻止其发挥作用。CRL3对Nrf2的抑制作用可被SQSTM1/p62减弱，而SQSTM1/p62的磷酸化会增强这种减弱作用。SCF的抑制作用需要GSK3对Nrf2进行磷酸化，而PKB/Akt和其他激酶可抑制GSK3的活性。我们讨论了在不同情况下泛素连接酶如何控制Nrf2的活性。我们还描述了使CRL3失活以减轻应激并恢复体内平衡的内源性信号分子。
