PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex

J Biol Chem. 2006 Dec 8;281(49):37893-903. doi: 10.1074/jbc.M606539200. Epub 2006 Oct 17.

Abstract

Keap1 is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress. Inhibition of Keap1-dependent ubiquitination of the bZIP transcription factor Nrf2 enables Nrf2 to activate a cyto-protective transcriptional program that counters the damaging effects of oxidative stress. In this report we have identified a member of the phosphoglycerate mutase family, PGAM5, as a novel substrate for Keap1. The N terminus of the PGAM5 protein contains a conserved NXESGE motif that binds to the substrate binding pocket in the Kelch domain of Keap1, whereas the C-terminal PGAM domain binds Bcl-X(L). Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Quinone-induced oxidative stress and the chemopreventive agent sulforaphane inhibit Keap1-dependent ubiquitination of PGAM5. The identification of PGAM5 as a novel substrate of Keap1 suggests that Keap1 regulates both transcriptional and post-transcriptional responses of mammalian cells to oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Autoantigens
  • Binding Sites
  • COS Cells
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Chlorocebus aethiops
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • Membrane Proteins
  • Molecular Sequence Data
  • Oxidation-Reduction
  • Phylogeny
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Transfection
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Autoantigens
  • Cell Cycle Proteins
  • GOLGA4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Membrane Proteins
  • Recombinant Proteins
  • bcl-X Protein
  • Ubiquitin-Protein Ligases