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J. Biol. Chem., Vol. 280, Issue 34, 30091-30099, August 26, 2005

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Ubiquitination of Keap1, a BTB-Kelch Substrate Adaptor Protein for Cul3, Targets Keap1 for Degradation by a Proteasome-independent Pathway^*

Donna D. Zhang, Shih-Ching Lo, Zheng Sun, Geetha M. Habib, Michael W. Lieberman, and Mark Hannink¶

From the Department of Biochemistry, University of Missouri, Columbia, Missouri 65212 and the Department of Pathology, Baylor College of Medicine, Houston, Texas 77030

Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome. Inhibition of Keap1-dependent ubiquitination of Nrf2 increases steady-state levels of Nrf2 and enables activation of cytoprotective Nrf2-dependent genes. In this report, we demonstrate that Keap1 and three other BTB-Kelch proteins, including GAN1, ENC1, and Sarcosin, are ubiquitinated by a Cul3-dependent complex. Ubiquitination of Keap1 is markedly increased in cells exposed to quinone-induced oxidative stress, occurs in parallel with inhibition of Keap1-dependent ubiquitination of Nrf2, and results in decreased steady-state levels of Keap1, particularly in cells that are unable to synthesize glutathione. Degradation of Keap1 is independent of the 26 S proteasome, because inhibitors of the 26 S proteasome do not prevent loss of Keap1 following exposure of cells to quinone-induced oxidative stress. Our results suggest that a switch from substrate to substrate adaptor ubiquitination is a critical regulatory step that controls steady-state levels of both BTB-Kelch substrate adaptor proteins and their cognate substrates.

Received for publication, February 3, 2005 , and in revised form, June 14, 2005.

^* This work was supported by the University of Missouri Molecular Biology Program, the University of Missouri Food for the 21st Century program, National Institutes of Health Research Grant 1-RO1-GM59213 and Development Project in P50-CA103130 (to M. H.), and by a grant from the University of Missouri Research Board. 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.

^¶ To whom correspondence should be addressed: Life Sciences Center, University of Missouri, 1201 E. Rollins St., Columbia, MO 65212. Tel.: 573-882-7971; Fax: 573-884-4597; E-mail: hanninkm{at}missouri.edu.

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