Nrf2Keap1signalvejen

The Nrf2-Keap1 signaling pathway is a critical cellular defense mechanism that regulates the expression of a vast array of antioxidant and cytoprotective genes. At its core is the transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2). Under basal conditions, Nrf2 is typically sequestered in the cytoplasm by its inhibitory binding protein, Keap1 (Kelch-like ECH-associated protein 1). Keap1 acts as a negative regulator, targeting Nrf2 for ubiquitination and subsequent degradation by the proteasome.

However, when the cell encounters oxidative or electrophilic stress, reactive oxygen species (ROS) or electrophiles modify specific cysteine residues on Keap1. These modifications cause a conformational change in Keap1, disrupting its ability to bind and degrade Nrf2. This stabilization of Nrf2 allows it to translocate into the nucleus.

Once in the nucleus, Nrf2 heterodimerizes with small Maf (musculoaponeurotic fibrosarcoma oncogene homolog) proteins and binds to specific DNA sequences known as antioxidant response elements (AREs) or electrophile response elements (EpREs) located in the promoter regions of target genes. This binding event then initiates the transcription of genes involved in a wide range of cellular defense processes. These include enzymes that detoxify harmful compounds, antioxidants that neutralize ROS, proteins involved in DNA repair, and those that regulate inflammatory responses.

The Nrf2-Keap1 pathway plays a significant role in protecting cells from damage caused by environmental toxins, inflammation, and metabolic dysfunction. Dysregulation of this pathway has been implicated in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions. Consequently, understanding and modulating this pathway is a promising avenue for therapeutic interventions.