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The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo

Ayumi Kuga1, Kouhei Tsuchida1, Harit Panda1

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

Molecular and Cellular Biology
|June 8, 2022
PubMed

Insights

The Keap1-mediated and β-TrCP-mediated pathways regulate Nrf2 activity. A specific Nrf2 mutation revealed β-TrCP pathway cooperation, particularly when Keap1 is profoundly suppressed, leading to esophageal hyperplasia.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that activates cytoprotective genes.
  • Nrf2 activity is primarily regulated by two protein degradation pathways: Keap1-mediated and β-TrCP-mediated.
  • Understanding the interplay between these degradation pathways is crucial for comprehending Nrf2 regulation.

Purpose of the Study:

  • To investigate the relative contributions of the Keap1-mediated and β-TrCP-mediated pathways in regulating Nrf2 activity.
  • To characterize the physiological consequences of disrupting the β-TrCP-mediated Nrf2 degradation pathway.
  • To elucidate the cooperative roles of Keap1 and β-TrCP in controlling Nrf2 levels and function.

Main Methods:

  • Generation of knock-in mouse lines expressing an Nrf2 mutant (Nrf2SA) with substitutions affecting β-TrCP interaction.
  • Crossbreeding Nrf2SA mutant mice with Keap1 knockdown mouse models at varying knockdown levels.
  • Assessment of Nrf2 levels, Nrf2 activity, and phenotypic changes including growth and tissue morphology.

Main Results:

  • Homozygous Nrf2SA mice exhibited normal growth and Nrf2 levels under unstressed conditions.
  • Suppression of Keap1 activity led to significantly higher Nrf2 accumulation in Nrf2SA macrophages compared to wild-type.
  • Profound Keap1 knockdown in Nrf2SA mice resulted in severe growth retardation and esophageal hyperplasia/hyperkeratosis, linked to increased Nrf2 activity.
  • Moderate Keap1 suppression did not cause evident growth retardation or activation abnormalities.

Conclusions:

  • The β-TrCP-mediated pathway cooperates with the Keap1-mediated pathway in regulating Nrf2 activity.
  • This cooperation is most apparent and physiologically significant when the Keap1-mediated pathway is profoundly suppressed.
  • Disruption of β-TrCP-mediated Nrf2 regulation, especially under conditions of severe Keap1 deficiency, can lead to specific pathological changes, notably in the esophageal epithelium.
Keywords:
Keap1Nrf2degradationβ-TrCP

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