The Keap1-BTB Protein Is an Adaptor That Bridges Nrf2 to a Cul3-Based E3 Ligase: Oxidative Stress Sensing by a Cul3-Keap1 Ligase

• DOI: 10.1128/mcb.24.19.8477-8486.2004
• Publication Date: 2004-09-14T19:58:18Z
• Authors: Sara B. Cullinan; John D. Gordan; Jianping Jin; J. Wade Harper; J. Alan Diehl
• Keywords: KEAP1; Proteolysis

The Nrf2 transcription factor promotes survival following cellular insults that trigger oxidative damage.Nrf2 activity is opposed by the BTB/POZ domain protein Keap1.Keap1 proposed to regulate strictly through its capacity inhibit nuclear import.Recent work suggests inhibition of may also depend upon ubiquitin-mediated proteolysis.To address contribution Keap1-dependent sequestration versus proteolysis, we identified E3 ligase regulates ubiquitination.We demonstrate Keap1 not solely a cytosolic anchor; rather, an adaptor bridges Cul3.We Cul3-Keap1 complexes polyubiquitination both in vitro and vivo.Inhibition either or Cul3 increases accumulation, leading promiscuous activation Nrf2dependent gene expression.Our data restrains via target cytoplasmic Cul3-based suggest model which coordinately accumulation access genes.