PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria.
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).
Lo
Shih-Ching
SC
Department of Biochemistry, University of Missouri - Columbia, Columbia, MO 65212, USA.
Hannink
Mark
M
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010736:Phosphoglycerate Mutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D020033:Protein Isoforms / Q000378:metabolism; D021382:Protein Sorting Signals
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; D020033:Protein Isoforms; D021382:Protein Sorting Signals; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases; D010736:Phosphoglycerate Mutase