KEAP1independent

KEAP1independent is a term used to describe regulatory mechanisms that influence NRF2 activity without involving KEAP1 as the primary regulator. The canonical NRF2 pathway centers on KEAP1, which binds NRF2 in the cytoplasm and promotes its ubiquitination by the CUL3-RBX1 E3 ligase, leading to proteasomal degradation. Under oxidative or electrophilic stress, KEAP1 undergoes modification and releases NRF2, allowing NRF2 to accumulate in the nucleus and activate antioxidant response element-driven genes.

KEAP1independent regulatory mechanisms modulate NRF2 through alternate routes that do not rely on KEAP1. Examples include phosphorylation by kinases such as PKC, MAPK, and PI3K-AKT that can promote NRF2 stabilization, nuclear translocation, or transcriptional activity even when KEAP1 is present. Endoplasmic reticulum stress can activate PERK, which can phosphorylate NRF2 and enhance its stability and activity independent of KEAP1. The GSK-3β/β-TrCP axis provides another KEAP1independent control point: GSK-3β–mediated phosphorylation creates a degron recognized by β-TrCP, leading to KEAP1-independent degradation of NRF2. Additionally, transcriptional upregulation of the NFE2L2 gene or post-transcriptional NRF2 mRNA stabilization can increase NRF2 output without KEAP1 involvement. Other E3 ligases may participate in KEAP1independent turnover of NRF2 under certain conditions.

Understanding KEAP1independent regulation has implications for redox biology and disease, including contexts where KEAP1 is mutated or dysfunctional, and for developing therapies that target NRF2 activity beyond the canonical KEAP1 sensor.