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PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria*

Posted by on in 2008
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Lo, Shih-Ching a, b and Mark Hannink, a, b, 2008, Experimental Cell Research 314:1789-1803.

aDepartment of Biochemistry, University of Missouri – Columbia, Columbia, MO 65212, USA bThe Christopher S. Bond Life Sciences Center, University of Missouri – Columbia, Columbia, MO 65212, USA

Abstract

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).

*Note:  The anti-IgY agarose used in this publication was manufactured by Gallus Immunotech Inc.

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