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The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway.

Liam Baird1, Masayuki Yamamoto2,3

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.

Molecular and Cellular Biology
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The KEAP1-NRF2 pathway protects cells from stress. Stress allows the transcription factor NRF2 to activate protective genes, offering therapeutic potential for various diseases.

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E3 ubiquitin ligaseKEAP1NRF2antioxidantoxidative stressstress response

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is crucial for cellular defense against oxidative and electrophilic stress.
  • Under normal conditions, KEAP1 targets NRF2 for degradation, maintaining low NRF2 levels.
  • Stress disrupts this interaction, enabling NRF2 accumulation and activation of antioxidant genes.

Purpose of the Study:

  • To elucidate the intricate regulatory mechanisms of the KEAP1-NRF2 pathway.
  • To highlight the role of NRF2 activation in diverse cellular signaling and metabolic pathways.
  • To underscore the therapeutic potential of modulating NRF2 activity for noncommunicable diseases.

Main Methods:

  • Review of recent advances in understanding KEAP1-NRF2 pathway regulation.
  • Analysis of molecular mechanisms involving KEAP1 stress sensors and NRF2 degradation.
  • Integration of signaling and metabolic pathway crosstalk with NRF2 activity.

Main Results:

  • KEAP1 acts as a multi-sensor, integrating various cellular inputs to control NRF2 activity.
  • Stress triggers NRF2 stabilization and nuclear translocation, initiating the antioxidant response.
  • KEAP1 inactivation modalities allow diverse cellular signals to modulate NRF2.

Conclusions:

  • The KEAP1-NRF2 pathway is a critical hub for cellular stress response.
  • NRF2 activation is implicated in numerous disease phenotypes.
  • Targeting NRF2 offers a promising therapeutic strategy for a wide range of noncommunicable diseases.