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Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway.

Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome. Inhibition of Keap1-dependent ubiquitination of Nrf2 increases steady-state levels of Nrf2 and enables activation of cytoprotective Nrf2-dependent genes. In this report, we demonstrate that Keap1 and three other BTB-Kelch proteins, including GAN1, ENC1, and Sarcosin, are ubiquitinated by a Cul3-dependent complex. Ubiquitination of Keap1 is markedly increased in cells exposed to quinone-induced oxidative stress, occurs in parallel with inhibition of Keap1-dependent ubiquitination of Nrf2, and results in decreased steady-state levels of Keap1, particularly in cells that are unable to synthesize glutathione. Degradation of Keap1 is independent of the 26 S proteasome, because inhibitors of the 26 S proteasome do not prevent loss of Keap1 following exposure of cells to quinone-induced oxidative stress. Our results suggest that a switch from substrate to substrate adaptor ubiquitination is a critical regulatory step that controls steady-state levels of both BTB-Kelch substrate adaptor proteins and their cognate substrates.

Pubmed ID: 15983046


  • Zhang DD
  • Lo SC
  • Sun Z
  • Habib GM
  • Lieberman MW
  • Hannink M


The Journal of biological chemistry

Publication Data

August 26, 2005

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 1-R01-GM59213
  • Agency: NCI NIH HHS, Id: P50-CA103130

Mesh Terms

  • Animals
  • COS Cells
  • Cell Cycle Proteins
  • Cell Line
  • Chitin
  • Cullin Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Genetic Vectors
  • Glutathione
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • NF-E2-Related Factor 2
  • Oxidative Stress
  • Proteasome Endopeptidase Complex
  • Proteins
  • Quinones
  • Recombinant Proteins
  • Trans-Activators
  • Transfection
  • Ubiquitin