Nrf2 Activation


The mechanism of Nrf2 (Nuclear Factor-E2 related) activation and Nrf2-mediated antioxidant responses in the lungs. Under unstressed conditions, Keap1 protein traps Nrf2 in the cytoplasm and targets this protein for the Cul3-Rbx1 ubiquitination system, which promotes the proteolysis of Nrf2 by the 26S proteasome. Diverse oxidative insults or pharmacological Nrf2 activators impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, promote newly synthesized Nrf2 to translocate to nucleus, and induce ARE-driven cytoprotective gene expression. Several accepted mechanisms include the modification of cysteine in Keap1: (a) Keap1 dissociation, (b) Keap1 hinge and latch, and © Keap1 ubiquitination. (2) There are also Keap1-independent pathways, among which protein kinases including PI3K, MAPKs, PKC, and GSK-3 play an essential role in phosphorylation of Nrf2 to increase its stability and transactivation activity. (3) Moreover, a noncanonical pathway induces Nrf2 activation by autophagy, which declares that p62 competes with Nrf2 for Keap1 binding, sequesters Keap1 into the autophagosome, and promotes its degradation. After de novo synthesized Nrf2 translocates to the nucleus, it heterodimerizes with small Maf then binds to ARE in the regulatory regions of Nrf2 target genes to induce their expression, which confer protective effects to various pulmonary diseases including BPD, respiratory infection, ARDS, COPD, asthma, IPF, and lung cancer.1)

The response of Nrf2 to oxidative challenge stress rapidly occurs mainly through phosphorylation at Ser40; protein kinase Cδ (PKCδ) induces activation of phosphorylation of Nrf2 at the residue, and the phosphorylated form is then released from Keap-1 and is stabilized for antioxidant response element (ARE)-driven gene expression 2).

1) Role of Nrf2 and Its Activators in Respiratory Diseases, Liu, Qinmei Gao, Yun Ci, Xinxin (2019), Oxidative Medicine and Cellular Longevity
2) AMPK Facilitates Nuclear Accumulation of Nrf2 by Phosphorylating at Serine 550, Min Sung Joo (2016), Molecular and cell biology ,