Role of Nrf2 and Its Activators in Cardiocerebral Vascular Disease

Figure 2

Stress response regulatory network of Nrf2. (a) Under basal conditions, Keapl is associated with Cul3 to form a homodimer through BTB/BTB domain interactions. Each Kelch/DGR domain interacts with the DLG and ETGE motifs of Nrf2. Nrf2 is polyubiquitinated and degraded by the proteasome through formation of a Cul3-Keap1 ligase complex. Ub represents ubiquitination. (b) To respond to OS, the key cysteine residues in Keap1 sense OS and disrupt the interaction between the DLGex and Kelch domains, thereby releasing Nrf2. Free Nrf2 transfers to the nucleus and forms a heterodimer with the sMaf protein, subsequently binding to the ARE and initiating the transcription of downstream antioxidant and detoxifying enzyme genes. Kinases PI3K, PKC, JNK, and ERK activate Nrf2 by phosphorylation. GSK-3β can promote Nrf2 translocation from the nucleus through Fyn kinase activation and lead to the deactivation of Nrf2 in the nucleus. p38-MAPK and GSK-3β inhibit Nrf2 activation. OS regulates p62 through phosphorylation, and phosphorylated p62 binds to Keap1, resulting in the autophagic degradation of Keap1. Under normal conditions, Bach1 (BTB and CNC homology 1) forms a heterodimer with the sMaf protein and thereby suppresses Nrf2 activation. miRNAs, such as miR-27a, miR-142-5p, and miR-153, can affect the level of Nrf2 protein in a Keap1-independent manner. p: phosphorylation.