Figure 5.

Model of drug-mediated γ-globin activation via NRF2 stabilization. Under basal conditions, NRF2 is sequestered in the cytoplasm by Keap1 dimers, ubiquitinated by the Cul3-Rbx1 ubiquitin ligase E3 complex, and targeted for proteasome-dependent degradation (left side). Treatment with tBHQ, simvastatin and DMF result in chemical modification of the repressor protein Keap1 at cysteine residue 151 which changes the conformation of Keap1 and facilitates NRF2 stabilization and nuclear translocation (right side). Subsequent heterodimerization with small Maf proteins mediates binding of NRF2 to the γ-globin promoter ARE (antioxidant response element) located at -100 base pairs upstream of the cap site.

NRF2: Nuclear factor (erythroid-derived 2)-like 2; Keap1: Kelch-like ECH-associated protein1; DMF: dimethylfumarate; tBHQ: tert-butylhydroquinone; ARE: antioxidant response element