Endogenous production and exposure to oxidising molecules is continuous. The continuous production of antioxidants in cells maintain a normal healthy antioxidant-inflammatory balance. Nrf2 (NF-E2-related factor 2), is a transcription factor that regulates genes for antioxidant and repair enzymes that protect cells from oxidative stress. But, oxidative stress defined as a condition endangering health, is not required to elevate Nrf2 activity. Instead, in unstressed cells, Nrf2 activity increases and decreases within a normal range of antioxidants and oxidants produced by metabolism, which we refer to as redox homeostasis. Activation of Nrf2 accounts for both the enhanced synthesis of endogenous antioxidants and increased activities of antioxidant enzymes. Keap1 is the regulator of Nrf2 and actual sensor of oxidants. Nrf2 must also be phosphorylated to enter the nucleus where it then binds to specific sequences in DNA. The binding, activation of transcription, and the deactivation of Nrf2 are regulated through interactions partner transcription factors, c-Jun and small Mafs, and inhibitors of Nrf2-regulated gene expression, c-Myc and Bach1. Keap1 is also regulated by cytosolic proteins including p62 that can activate Nrf2 in a non-canonical manner. In prolonged exposure to oxidative or inflammatory stimuli that produce stress, Nrf2 activation is increased in an attempt to maintain redox homeostasis; however, constant stress can lead to a new steady state that we associate with chronic disease. In ageing, loss of the ability to activate Nrf2 may contribute to age-related pathologies including Huntington’s disease, other neurodegenerative diseases, and decreased resistance to environmental toxicants.
- oxidative stress