Figure 2.

Mechanism of Nrf2 activation dependent on S349 phosphorylation of p62. Left: under basal conditions, Keap1, in collaboration with the Cul3/Rbx1 E3 ubiquitin ligase complex, promotes the proteasomal degradation of Nrf2. Upon oxidative stress, Keap1 oxidation results in the liberation of Nrf2 and its translocation to the nucleus, where it promotes the expression of a battery of target genes encoding antioxidant proteins and anti‐inflammatory enzymes. Right: phosphorylated p62 interacts with the Nrf2‐binding site of Keap1 and competitively inhibits the Keap1–Nrf2 interaction, resulting in the expression of Nrf2 target genes, which include p62. Therefore, Ser349 phosphorylated p62 causes the constitutive activation of Nrf2.