Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase
Open Access
- 27 May 2008
- journal article
- review article
- Published by Springer Nature in Cell Research
- Vol. 18 (6), 609-621
- https://doi.org/10.1038/cr.2008.61
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).Keywords
This publication has 98 references indexed in Scilit:
- Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteinsProceedings of the National Academy of Sciences, 2007
- Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to InsigProceedings of the National Academy of Sciences, 2007
- Protein Sensors for Membrane SterolsCell, 2006
- Gp78, a Membrane-Anchored Ubiquitin Ligase, Associates with Insig-1 and Couples Sterol-Regulated Ubiquitination to Degradation of HMG CoA ReductaseMolecular Cell, 2005
- Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterolCell Metabolism, 2005
- Insig-dependent Ubiquitination and Degradation of Mammalian 3-Hydroxy-3-methylglutaryl-CoA Reductase Stimulated by Sterols and GeranylgeraniolJournal of Biological Chemistry, 2003
- Cholesterol Addition to ER Membranes Alters Conformation of SCAP, the SREBP Escort Protein that Regulates Cholesterol MetabolismMolecular Cell, 2002
- The Ubiquitin-Proteasome Pathway Mediates the Regulated Degradation of Mammalian 3-Hydroxy-3-methylglutaryl-coenzyme A ReductaseJournal of Biological Chemistry, 2000
- Transport-Dependent Proteolysis of SREBPCell, 1999
- Regulation of the mevalonate pathwayNature, 1990