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

[11] REGULATION OF THE MEVALONATE PATHWAY [J].

GOLDSTEIN, JL ;

BROWN, MS .

NATURE, 1990, 343 (6257) :425-430

[12] The ubiquitin system [J].

Hershko, A ;

Ciechanover, A .

ANNUAL REVIEW OF BIOCHEMISTRY, 1998, 67 :425-479

[13] The IκB-NF-κB signaling module:: Temporal control and selective gene activation [J].

Hoffmann, A ;

Levchenko, A ;

Scott, ML ;

Baltimore, D .

SCIENCE, 2002, 298 (5596) :1241-1245

[14] 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

[15] Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [J].

Horton, JD ;

Shah, NA ;

Warrington, JA ;

Anderson, NN ;

Park, SW ;

Brown, MS ;

Goldstein, JL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (21) :12027-12032

[16] TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains [J].

Kanayama, A ;

Seth, RB ;

Sun, LJ ;

Ea, CK ;

Hong, M ;

Shaito, A ;

Chiu, YH ;

Deng, L ;

Chen, ZJ .

MOLECULAR CELL, 2004, 15 (04) :535-548

[17] The sterol-sensing domain: multiple families, a unique role? [J].

Kuwabara, PE ;

Labouesse, M .

TRENDS IN GENETICS, 2002, 18 (04) :193-201

[18] Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1 [J].

Lee, JN ;

Ye, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (43) :45257-45265

[19] Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2 [J].

Lee, PCW ;

Sever, N ;

DeBose-Boyd, RA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (26) :25242-25249

[20]

METHERALL JE, 1989, J BIOL CHEM, V264, P15634

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