FIG. 5.

Regulation of the Cul3–Keap1–E3 ligase complex. The Cul3–Keap1–E3 ligase complex is active when it is in the neddylated state, which facilitates the docking of a Keap1 homodimer-bound to Nrf2 into the complex, resulting in ubiquitination and degradation of Nrf2. The complex is inactivated by deneddylation. The CSN complex removes Nedd8 from Cul3 enhancing the association of Cul3 and CAND1, which triggers dissociation of Keap1-Nrf2 from Cul3. Finally, neddylation can reactivate the E3 ligase complex. The complex can also be reactivated following deneddylation without disassembly of the complex. UBC12 can conjugate Nedd8 back onto Cul3 without dissociation of Keap1 from the Cul3–Rbx1 core complex (red arrow).