The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a

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Published on: March 14, 2019

Sara B Cullinan1, John D Gordan, Jianping Jin

  • 1The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania Cancer Center, 454 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA.

Molecular and Cellular Biology
|September 16, 2004
PubMed

Insights

The Keap1 protein restrains the Nrf2 transcription factor by targeting it for degradation via a Cul3-based E3 ligase. This mechanism controls Nrf2 accumulation and activation, crucial for cellular protection against oxidative stress.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor vital for cellular survival against oxidative damage.
  • Kelch-like ECH-associated protein 1 (Keap1) opposes Nrf2 activity, primarily through inhibiting its nuclear import.
  • Emerging evidence suggests Nrf2 inhibition also involves ubiquitin-mediated proteolysis.

Purpose of the Study:

  • To investigate the contribution of Keap1-dependent sequestration versus proteolysis in Nrf2 regulation.
  • To identify the specific E3 ligase responsible for Nrf2 ubiquitination.
  • To elucidate the mechanism by which Keap1 controls Nrf2 activity.

Main Methods:

  • Biochemical assays to identify the E3 ligase.
  • In vitro and in vivo experiments to study Nrf2 ubiquitination.
  • Analysis of Nrf2 nuclear accumulation and gene expression following inhibition of Keap1 or Cul3.

Main Results:

  • Keap1 acts as an adaptor, bridging Nrf2 to Cullin 3 (Cul3).
  • Cul3-Keap1 complexes mediate Nrf2 polyubiquitination both in vitro and in vivo.
  • Inhibiting Keap1 or Cul3 enhances Nrf2 nuclear entry and promiscuous gene activation.

Conclusions:

  • Keap1 restrains Nrf2 by targeting it to a cytoplasmic Cul3-based E3 ligase.
  • This mechanism regulates both Nrf2 accumulation and its access to target genes.
  • Keap1 plays a dual role in controlling Nrf2 activity, involving both sequestration and proteolysis.

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