Fig. 3
From: A state-of-the-art review on the NRF2 in Hepatitis virus-associated liver cancer
Keap1/Nrf2 signaling's depiction of its regulatory processes. A negative effect on Nrf2, Nrf1, and Nrf3 expression. In standard settings, proteasome activity keeps Nrf2 expression at a modest level. Keap1 binds to and sequesters Nrf2 in the cytosol, which is then ubiquitinated by the Keap1-Cul3-Ring-box1 protein (Rbx1, also called Roc1) complex and then degraded by the proteasome. Glycogen synthase kinase 3 (GSK-3) inhibits Nrf2 function and may promote the degradation of Nrf2. To recruit the E3 ligase adapter-TrCP, GSK-3 phosphorylates Nrf2. The ubiquitin-proteasome degradation of Nrf2 is triggered by GSK-3/-TrCP, although it does not need Keap1. 4) Positive regulation of Nrf2: when ROS levels are high, Nrf2 is unbound from Keap1 and moves to the nucleus, where it activates antioxidant genes, including Heme oxygenase 1 (HO1) and NAD(P)H dehydrogenase (Quinone) 1 (NQO1). In response to oxidative stress, Nrf2 dissociates from Keap1 and moves to the nucleus, which associates with sMaf to form a heterodimer. By binding to ARE sequences, heterodimeric Nrf2-sMaf transcription factors stimulate the production of antioxidant genes. Instead, cytoprotective gene expression is suppressed when Nrf2 is phosphorylated by GSK-3 because -TrCP facilitates Nrf2's association with a Cul1 ubiquitin ligase complex (Skp1-Cul1-Rbx1/Roc1) [20, 74]