TY - JOUR
T1 - Insig-dependent ubiquitination and degradation of 3-hydroxy-3- methylglutaryl coenzyme A reductase stimulated by δ- and γ-tocotrienols
AU - Song, Bao Liang
AU - DeBose-Boyd, Russell A.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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 HMGCoA reductase is also stimulated by various forms of vitamin E, a generic term for α-, β-, δ-, and γ-tocopherols and tocotrienols, which are primarily recognized for their potent antioxidant activity. Here, we show that δ-tocotrienol stimulates ubiquitination and degradation of reductase and blocks processing of sterol regulatory element-binding proteins (SREBPs), another sterol-mediated action of Insigs. The γ-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 γ- and δ-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.
AB - 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 HMGCoA reductase is also stimulated by various forms of vitamin E, a generic term for α-, β-, δ-, and γ-tocopherols and tocotrienols, which are primarily recognized for their potent antioxidant activity. Here, we show that δ-tocotrienol stimulates ubiquitination and degradation of reductase and blocks processing of sterol regulatory element-binding proteins (SREBPs), another sterol-mediated action of Insigs. The γ-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 γ- and δ-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.
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U2 - 10.1074/jbc.M605575200
DO - 10.1074/jbc.M605575200
M3 - Article
C2 - 16831864
AN - SCOPUS:33748744385
SN - 0021-9258
VL - 281
SP - 25054
EP - 25061
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 35
ER -