REVIEW

Cell Research (2008): 609-621
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Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase

Russell A DeBose-Boyd

Correspondence: Russell A DeBose-Boyd E-mail: Russell.DeBose-Boyd@utsouthwestern.edu

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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).

Cell Research (2008) 18:609-621. doi: 10.1038/cr.2008.61; published online 27 May 2008 7

Keywords: ubiquitination, cholesterol synthesis, feedback regulation, HMG CoA reductase, statin, Scap-SREBP, Insig, ER-associated degradation