PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex.
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.
Lo
Shih-Ching
SC
Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA.
Hannink
Mark
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens; D001665:Binding Sites; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010802:Phylogeny; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D001324:Autoantigens; D018797:Cell Cycle Proteins; C098772:GOLGA4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D011994:Recombinant Proteins; D051020:bcl-X Protein; D044767:Ubiquitin-Protein Ligases