The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Abstract

The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2’s cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.

NFE2L3 promotes malignant behavior and EMT of human hepatocellular carcinoma (HepG2) cells via Wnt/β‑catenin pathway

“…The level of NFE2L3 in placental, cornea, bladder is high, and other tissues are converse 9 . The homologous NFE2L2 has been proved to be a driver gene of malignant tumor, and it plays an excellent role in regulating oxidative stress 10 . NFE2L2 and NFE2L3 have been proved to be important mutant genes of 12 kinds of malignant tumors in genome sequencing work, and the number of related factors is 127 11 .…”

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger Cyclin K degradation

“…1A and 1C). NRF2 is a basic leucine zipper transcription factor that regulates the expression of genes encoding xenobiotic-detoxification or antioxidant enzymes 15 . In the absence of oxidative or electrophilic stress, NRF2 is degraded by the ubiquitin-proteasome system through binding to the E3 ubiquitin ligase KEAP1-CUL3-RBX1 15 .…”

“…NRF2 is a basic leucine zipper transcription factor that regulates the expression of genes encoding xenobiotic-detoxification or antioxidant enzymes 15 . In the absence of oxidative or electrophilic stress, NRF2 is degraded by the ubiquitin-proteasome system through binding to the E3 ubiquitin ligase KEAP1-CUL3-RBX1 15 . In lung and liver cancer patients, KEAP1 loss-of-function or NRF2 gain-of-function mutations are frequently observed 16,17 , suggesting that over-active NRF2 is a potential therapeutic target for these cancers.…”

“…NRF2 is a transcription factor that is polyubiquitinated by the CUL3-KEAP1 ubiquitin ligase and degraded by the proteasome under normal conditions 15 . Oxidative stress or xenobiotic exposure inactivates KEAP1 to stabilize NRF2, which subsequently activates expression of genes related to antioxidant response and xenobiotic detoxification 15 .…”

“…NRF2 is a transcription factor that is polyubiquitinated by the CUL3-KEAP1 ubiquitin ligase and degraded by the proteasome under normal conditions 15 . Oxidative stress or xenobiotic exposure inactivates KEAP1 to stabilize NRF2, which subsequently activates expression of genes related to antioxidant response and xenobiotic detoxification 15 . Clinically, KEAP1 mutations are frequently found in a variety of cancers 16,17 , raising the possibility that inhibiting overactive NRF2 may provide therapeutic benefits to patients with KEAP1 mutations.…”