Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis

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^Keap1, CRL4^DCAF11, SCF^β-TrCP, and Hrd1). CRL3^Keap1 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^Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCF^β-TrCP 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^Keap1 to alleviate stress and restore homeostasis.