Figure 3.

Regulation of Nrf2 activation in constitutive conditions and after ICH. Under constitutive conditions, Nrf2 is anchored to cytoplasmic actin by Kelch-like ECH-associated protein 1 (Keap1) homodimers. These also function as adaptor proteins for Cullin 3 (Cul3)-dependent E3 ubiquitin ligase complex RING box protein 1 (Rbx1) which ubiquitinates Nrf2, leading to its proteasomal degradation. BTB and CNC homology (Bach) proteins bind nuclear small Maf (sMaf) protein and repress expression of certain antioxidant genes. During conditions of oxidative stress or haem accumulation, as may occur after ICH, Keap1 loses its’ substrate adaptor activity and becomes saturated with Nrf2. Nrf2 levels rise and Nrf2 localises to the nucleus where it heterodimerises with sMaf proteins to transactivate genes containing an antioxidant response element (ARE) motif. Simultaneously, haem binding of Bach proteins prevents heterodimer formation with sMaf proteins and induces nuclear export of Bach by chromosomal maintenance 1 (Crm1). Created with BioRender.com.