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

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188 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)609-621
Number of pages13
JournalCell Research
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • Cholesterol synthesis
  • ERassociated degradation
  • Feedback regulation
  • HMG CoA reductase
  • Insig
  • Scap-SREBP
  • Statin
  • Ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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