Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase

被引:292
作者
DeBose-Boyd, Russell A. [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
关键词
ubiquitination; cholesterol synthesis; feedback regulation; HMG CoA reductase; statin; Scap-SREBP; Insig; ER-associated degradation;
D O I
10.1038/cr.2008.61
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant amount of feedback control through multiple mechanisms that are mediated by sterol and nonsterol end-products of mevalonate metabolism. Here, I will discuss recent advances that shed light on one mechanism for control of reductase, which involves rapid degradation of the enzyme. Accumulation of certain sterols triggers binding of reductase to endoplasmic reticulum (ER) membrane proteins called Insig-1 and Insig-2. Reductase-Insig binding results in recruitment of a membrane-associated ubiquitin ligase called gp78, which initiates ubiquitination of reductase. This ubiquitination is an obligatory reaction for recognition and degradation of reductase from ER membranes by cytosolic 26S proteasomes. Thus, sterol-accelerated degradation of reductase represents an example of how a general cellular process (ER-associated degradation) is used to control an important metabolic pathway (cholesterol synthesis).
引用
收藏
页码:609 / 619
页数:11
相关论文
共 35 条
[11]   Genetic analysis of hydroxymethylglutaryl-coenzyme A reductase regulated degradation [J].
Hampton, RY .
CURRENT OPINION IN LIPIDOLOGY, 1998, 9 (02) :93-97
[12]   Proteolysis and sterol regulation [J].
Hampton, RY .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2002, 18 :345-378
[13]   In vivo examination of membrane protein localization and degradation with green fluorescent protein [J].
Hampton, RY ;
Koning, A ;
Wright, R ;
Rine, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (02) :828-833
[14]   ER-associated degradation in protein quality control and cellular regulation [J].
Hampton, RY .
CURRENT OPINION IN CELL BIOLOGY, 2002, 14 (04) :476-482
[15]   SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver [J].
Horton, JD ;
Goldstein, JL ;
Brown, MS .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (09) :1125-1131
[16]   Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein [J].
Hua, XX ;
Nohturfft, A ;
Goldstein, JL ;
Brown, MS .
CELL, 1996, 87 (03) :415-426
[17]  
INOUE S, 1991, J BIOL CHEM, V266, P13311
[18]   The sterol-sensing domain: multiple families, a unique role? [J].
Kuwabara, PE ;
Labouesse, M .
TRENDS IN GENETICS, 2002, 18 (04) :193-201
[19]  
LISCUM L, 1985, J BIOL CHEM, V260, P522
[20]  
LUSKEY KL, 1985, J BIOL CHEM, V260, P271