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J. Biol. Chem., Vol. 281, Issue 49, 37893-37903, December 8, 2006

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PGAM5, a Bcl-X_L-interacting Protein, Is a Novel Substrate for the Redox-regulated Keap1-dependent Ubiquitin Ligase Complex^*

From the Department of Biochemistry, University of Missouri, Columbia, Missouri 65211

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.

Received for publication, July 10, 2006 , and in revised form, September 15, 2006.

^* This work was supported by National Institutes of Health Grant RO1 AT003899. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Life Sciences Center, University of Missouri, 1201 E. Rollins St., Columbia, MO 65211. Tel.: 573-882-7971; Fax: 573-884-3087; E-mail: hanninkm{at}missouri.edu.

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