Posttranslational Regulation of HMG CoA Reductase, the Rate-Limiting Enzyme in Synthesis of Cholesterol

The polytopic, endoplasmic reticulum (ER) membrane protein 3-hydroxy3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, the key intermediate in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). Transcriptional, translational, and posttranslational feedback mechanisms converge on this reductase to ensure cells maintain a sufficient supply of essential nonsterol isoprenoids but avoid overaccumulation of cholesterol and other sterols. The focus of this review is mechanisms for the posttranslational regulation of HMG CoA reductase, which include sterol-accelerated ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. We discuss how GGpp-induced ER-to-Golgi trafficking of the vitamin K2 synthetic enzyme UbiA prenyltransferase domain-containing protein-1 (UBIAD1) modulatesHMGCoA reductase ERAD to balance the synthesis of sterol and nonsterol isoprenoids. We also summarize the characterization of genetically manipulated mice, which established that sterol-accelerated, UBIAD1modulated ERAD plays a major role in regulation of HMG CoA reductase and cholesterol metabolism in vivo.

Automated summary

The text discusses the posttranslational regulation mechanisms of HMG-CoA reductase, including sterol-accelerated ubiquitination and ER-associated degradation, augmented by GGpp. By regulating the trafficking of proteins, cells maintain a suitable supply of isoprenoids while avoiding excessive accumulation of cholesterol.