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J. Biol. Chem., Vol. 281, Issue 35, 25054-25061, September 1, 2006

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Insig-dependent Ubiquitination and Degradation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Stimulated by - and -Tocotrienols^*

From the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046

Sterol-regulated ubiquitination marks 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-determining enzyme in cholesterol synthesis, for endoplasmic reticulum (ER)-associated degradation by 26 S proteasomes. This degradation, which results from sterol-induced binding of reductase to ER membrane proteins called Insigs, contributes to the complex, multivalent feedback regulation of the enzyme. Degradation of HMG-CoA reductase is also stimulated by various forms of vitamin E, a generic term for -, -, -, and -tocopherols and tocotrienols, which are primarily recognized for their potent antioxidant activity. Here, we show that -tocotrienol stimulates ubiquitination and degradation of reductase and blocks processing of sterol regulatory element-binding proteins (SREBPs), another sterol-mediated action of Insigs. The -tocotrienol analog is more selective in enhancing reductase ubiquitination and degradation than blocking SREBP processing. Other forms of vitamin E neither accelerate reductase degradation nor block SREBP processing. In vitro assays indicate that - and -tocotrienol trigger reductase ubiquitination directly and do not require further metabolism for activity. Taken together, these results provide a biochemical mechanism for the hypocholesterolemic effects of vitamin E that have been observed in animals and humans.

Received for publication, June 9, 2006 , and in revised form, July 7, 2006.

^* This work was supported in part by Grant HL20948 from the National Institutes of Health and the Perot Family Foundation. 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 may be addressed: Inst. of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. E-mail: BLSONG{at}sibs.ac.cn. ² Recipient of National Institutes of Health Mentored Minority Faculty Development Award HL70441, an Established Investigator Award from the American Heart Association (0540128N), and a Distinguished Young Scholar in Medical Research Award from the W. M. Keck Foundation. To whom correspondence may be addressed. E-mail: Russell.DeBose-Boyd{at}utsouthwestern.edu.

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