Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake

被引：208

作者：

Gong, Y ^{[1
]}

Lee, JN ^{[1
]}

Lee, PCW ^{[1
]}

Goldstein, JL ^{[1
]}

Brown, MS ^{[1
]}

Ye, J ^{[1
]}

机构：

[1] Univ Texas, SW Med Ctr, Dept Mol Genet, Dallas, TX 75390 USA

来源：

CELL METABOLISM | 2006年 / 3卷 / 01期

关键词：

D O I：

10.1016/j.cmet.2005.11.014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

This paper describes a convergent mechanism for the feedback control of cholesterol synthesis and uptake mediated by SREBPs, membrane bound transcription factors. Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. In sterol-overloaded cells, Scap/SREBP binds to Insig-1, which retains the complex in the ER. Upon sterol deprivation, the Scap/SREBP complex dissociates from Insig-1, which is then ubiquitinated on lysines 156 and 158 and degraded in proteasomes. Scap/SREBP moves to the Golgi, where SREBP is processed to liberate a nuclear fragment that activates genes for cholesterol synthesis and uptake and the gene for Insig-1. Ubiquitination is not necessary for release of Scap/SREBP from Insig-1, but it establishes a requirement for synthesis of new Insig-1 for feedback inhibition. When the new Insig-1 and cholesterol converge on Scap, Scap/SREBP binds to Insig-1, preventing ubiquitination. The Insig-1/Scap/SREBP complex accumulates in the ER, ready for liberation when the cell is again sterol deprived.

引用

页码：15 / 24

页数：10

共 32 条

[1] Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs [J].

Adams, CM ;

Reitz, J ;

De Brabander, JK ;

Feramisco, JD ;

Li, L ;

Brown, MS ;

Goldstein, JL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (50) :52772-52780

[2] Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption [J].

Altmann, SW ;

Davis, HR ;

Zhu, LJ ;

Yao, XR ;

Hoos, LM ;

Tetzloff, G ;

Iyer, SPN ;

Maguire, M ;

Golovko, A ;

Zeng, M ;

Wang, LQ ;

Murgolo, N ;

Graziano, MP .

SCIENCE, 2004, 303 (5661) :1201-1204

[3] Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism [J].

Brown, AJ ;

Sun, LP ;

Feramisco, JD ;

Brown, MS ;

Goldstein, JL .

MOLECULAR CELL, 2002, 10 (02) :237-245

[4] A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood [J].

Brown, MS ;

Goldstein, JL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11041-11048

[5]

CHEN ZJ, 2005, NAT CELL BIOL, V7, P1

[6] Schoenheimer effect explained - feedback regulation of cholesterol synthesis in mice mediated by Insig proteins [J].

Engelking, LJ ;

Liang, GS ;

Hammer, RE ;

Takaishi, K ;

Kuriyama, H ;

Evers, BM ;

Li, WP ;

Horton, JD ;

Goldstein, JL ;

Brown, MS .

JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (09) :2489-2498

[7] Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER [J].

Espenshade, PJ ;

Li, WP ;

Yabe, D .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (18) :11694-11699

[8] Membrane topology of human Insig-1, a protein regulator of lipid synthesis [J].

Feramisco, JD ;

Goldstein, JL ;

Brown, MS .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (09) :8487-8496

[9]

GOLDSTEIN JL, 1983, METHOD ENZYMOL, V98, P241

[10] Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis [J].

Goldstein, JL ;

Rawson, RB ;

Brown, MS .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2002, 397 (02) :139-148

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