Repression of Nrf2 by β-TrCP occurs in both a GSK-3-dependent and a GSK-3-independent manner
Nrf2 is subject to dual regulation by Keap1 and β-TrCP. The cartoon shows that Nrf2 is repressed by Keap1 though DLG and ETGE motifs in its Neh2 domain, both of which are required for ubiquitylation of the CNC-bZIP protein by Cul3-Rbx1. By contrast, Nrf2 is repressed by β-TrCP though DSGIS and DSAPGS motifs in its Neh6 domain, each of which is sufficient for ubiquitylation of the CNC-bZIP protein by Cul1-Rbx1. Phosphorylation of the DSGIS motif increases its degron activity, and this is positively regulated by GSK-3. The GSK-3 inhibitor CT99021 decreases the degron activity of the DSGIS destruction motif whereas PI3K and PKB/Akt inhibitors increase the degron activity of the DSGIS motif. By contrast, the DSAPGS destruction motif is not influenced by GSK-3 activity.