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PGAM5, a Bcl‐XL‐interacting protein, is a novel substrate for the redox‐regulated Keap1‐dependent ubiquitin ligase complex.
Author(s) -
Lo ShihChing,
Hannink Mark
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1022
Subject(s) - keap1 , phosphoglycerate mutase , ubiquitin ligase , ubiquitin , signal transducing adaptor protein , biochemistry , chemistry , deubiquitinating enzyme , microbiology and biotechnology , transcription factor , biology , signal transduction , enzyme , gene , glycolysis
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 cytoprotective 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, while the C‐terminal PGAM domain binds Bcl‐XL. Keap1‐dependent ubiquitination of PGAM5 results in proteosome‐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.