Sensing Oxidative Stress: The NRF2 Signaling Pathway

Cells are constantly exposed to a variety of both endogenous and exogenous oxidative and electrophilic insults that affect their biomolecules and compromise their function. Sensing the stress and mounting adaptive cytoprotective stress responses, particularly in a timely and controlled manner to remove the source of stress and repair the damaged components, are extremely important in maintaining cellular homeostasis and an organism’s wellbeing. The transcription factor nuclear factor erythroid-2 (NF-E2)-related factor 2 (NRF2) controls the expression of a set of genes that counteract oxidative and electrophilic stresses. Under physiological conditions, the protein levels of NRF2 are tightly controlled by Kelch-ECH associated protein 1 (KEAP1), a redox sensor and substrate adaptor for a Cullin 3-containing E3 ubiquitin ligase that ubiquitylates NRF2, targeting it for proteasomal degradation. During increased oxidative or electrophilic stress, KEAP1 cysteines are modified, resulting in a conformational change that prevents the ubiquitylation and degradation of NRF2. Newly synthesized NRF2 can then accumulate, translocate to the nucleus, and activate the transcription of antioxidant response element (ARE)-containing genes. This canonical activation of the NRF2 pathway involves the oxidative/electrophilic modification of KEAP1. However, NRF2 can also be activated through dysregulation of the autophagy pathway, namely the non-canonical mechanism of NRF2 activation. Non-canonical activation of NRF2 occurs independently of oxidative stress, and instead is a result of the direct interaction of KEAP1 and p62, an autophagy adaptor protein, and their aggregation in autophagosomes. This non-canonical mechanism of NRF2 activation results in prolonged activation of NRF2. Discovery of the non-canonical activation of NRF2, and the realization that certain cancer types have constitutively high levels of NRF2, have revealed that controlled, canonical activation of NRF2 is cytoprotective, whereas uncontrolled or prolonged activation is deleterious (“dark side” of NRF2). This chapter describes our current knowledge of the molecular mechanisms of NRF2 regulation, and the potential of NRF2-based strategies for disease prevention and therapeutic intervention.