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PMID: 18504457 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

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

Cell research ·Vol. 18 ·No. 6 ·2008-06-00 ·Pages 609-21

DeBose-Boyd RA

Abstract

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).

MeSH Terms
Animals Cholesterol/biosynthesis Feedback, Physiological Humans Hydroxymethylglutaryl CoA Reductases/metabolism Membrane Proteins/metabolism Protein Processing, Post-Translational Ubiquitination
Chemicals
Membrane Proteins Cholesterol Hydroxymethylglutaryl CoA Reductases
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
DeBose-Boyd Russell A
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. [email protected]
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Article Info
Journal
Cell research
Abbr.
Cell Res
ISSN
1748-7838
DOI
10.1038/cr.2008.61
Email
[email protected]
Published
2008-06-00
Pages
609-21
Language
English
Region
England
NLM ID
9425763
PMCID
PMC2742364
Subset
IM
Grants
NHLBI NIH HHS · P01 HL020948 · United States
NHLBI NIH HHS · P01 HL020948-310002 · United States
NHLBI NIH HHS · P01 HL020948-320002 · United States
NHLBI NIH HHS · HL20948 · United States
External Links
PubMed source DOI: 10.1038/cr.2008.61 PMC Full Text View journal details
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