PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria

• Published in: Experimental cell research 2008-05, Vol.314 (8), p.1789-1803
• Main Authors: Lo, Shih-Ching, Hannink, Mark
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Sequence; Animals; Anti-oxidant gene expression; Antioxidants; Binding sites; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cell Nucleus - genetics; Cellular biology; Chemoprevention; ENZYME ACTIVITY; Gene expression; Gene Expression Regulation; GENES; HOMEOSTASIS; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; LIGASES; MITOCHONDRIA; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial proteins; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Sequence Data; NF-E2-Related Factor 2 - metabolism; OXIDATION; Oxidative stress; OXIDIZERS; Phosphoglycerate Mutase - chemistry; Phosphoglycerate Mutase - genetics; Phosphoglycerate Mutase - metabolism; Phosphoprotein Phosphatases; Protein Isoforms - metabolism; Protein Sorting Signals; Proteins; SUBSTRATES; TRANSCRIPTION FACTORS; Ubiquitin ligases
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2008.02.014

Eukaryote cells balance production of reactive oxygen species (ROS) with levels of anti-oxidant enzyme activity to maintain cellular redox homeostasis. Mitochondria are a major source of ROS, while many anti-oxidant genes are regulated by the Nrf2 transcription factor. Keap1, a redox-regulated substrate adaptor for a cullin-based ubiquitin ligase, targets Nrf2 for proteosome-mediated degradation and represses Nrf2-dependent gene expression. We have previously identified a member of the phosphoglycerate mutase family, PGAM5, as a Keap1-binding protein. In this report, we demonstrate that PGAM5 is targeted to the outer membrane of mitochondria by an N-terminal mitochondrial-localization sequence. Furthermore, we provide evidence that PGAM5 forms a ternary complex containing both Keap1 and Nrf2, in which the dimeric Keap1 protein simultaneously binds both PGAM5 and Nrf2 through their conserved E(S/T)GE motifs. Knockdown of either Keap1 or PGAM5 activates Nrf2-dependent gene expression. We suggest that this ternary complex provides a molecular framework for understanding how nuclear anti-oxidant gene expression is regulated in response to changes in mitochondrial function(s).