Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system

• Published in: Molecular biology of the cell Vol. 23; no. 23; pp. 4484 - 4494
• Main Authors: Tsai, Yien Che, Leichner, Gil S., Pearce, Margaret M. P., Wilson, Gaye Lynn, Wojcikiewicz, Richard J. H., Roitelman, Joseph, Weissman, Allan M.
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 01.12.2012
• Subjects: Acyl Coenzyme A - genetics; Acyl Coenzyme A - metabolism; Animals; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - metabolism; Hydroxymethylglutaryl CoA Reductases - genetics; Hydroxymethylglutaryl CoA Reductases - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Receptors, Autocrine Motility Factor - genetics; Receptors, Autocrine Motility Factor - metabolism; Sterols - metabolism; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 1059-1524; 1939-4586; 1939-4586
• DOI: 10.1091/mbc.e12-08-0631

The endoplasmic reticulum (ER)–resident enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyzes the rate-limiting step in sterol production and is the therapeutic target of statins. Understanding HMG-CoA reductase regulation has tremendous implications for atherosclerosis. HMG-CoA reductase levels are regulated in response to sterols both transcriptionally, through a complex regulatory loop involving the ER Insig proteins, and posttranslationally, by Insig-dependent protein degradation by the ubiquitin-proteasome system. The ubiquitin ligase (E3) gp78 has been implicated in the sterol-regulated degradation of HMG-CoA reductase and Insig-1 through ER-associated degradation (ERAD). More recently, a second ERAD E3, TRC8, has also been reported to play a role in the sterol-accelerated degradation of HMG-CoA reductase. We interrogated this network in gp78 −/− mouse embryonic fibroblasts and also assessed two fibroblast cell lines using RNA interference. Although we consistently observe involvement of gp78 in Insig-1 degradation, we find no substantive evidence to support roles for either gp78 or TRC8 in the robust sterol-accelerated degradation of HMG-CoA reductase. We discuss factors that might lead to such discrepant findings. Our results suggest a need for additional studies before definitive mechanistic conclusions are drawn that might set the stage for development of drugs to manipulate gp78 function in metabolic disorders.