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

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 reduct...

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Autores principales: Tsai, Yien Che, Leichner, Gil S., Pearce, Margaret M. P., Wilson, Gaye Lynn, Wojcikiewicz, Richard J. H., Roitelman, Joseph, Weissman, Allan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510011/
https://www.ncbi.nlm.nih.gov/pubmed/23087214
http://dx.doi.org/10.1091/mbc.E12-08-0631
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author Tsai, Yien Che
Leichner, Gil S.
Pearce, Margaret M. P.
Wilson, Gaye Lynn
Wojcikiewicz, Richard J. H.
Roitelman, Joseph
Weissman, Allan M.
author_facet Tsai, Yien Che
Leichner, Gil S.
Pearce, Margaret M. P.
Wilson, Gaye Lynn
Wojcikiewicz, Richard J. H.
Roitelman, Joseph
Weissman, Allan M.
author_sort Tsai, Yien Che
collection PubMed
description 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.
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spelling pubmed-35100112013-02-16 Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system Tsai, Yien Che Leichner, Gil S. Pearce, Margaret M. P. Wilson, Gaye Lynn Wojcikiewicz, Richard J. H. Roitelman, Joseph Weissman, Allan M. Mol Biol Cell Articles 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. The American Society for Cell Biology 2012-12-01 /pmc/articles/PMC3510011/ /pubmed/23087214 http://dx.doi.org/10.1091/mbc.E12-08-0631 Text en © 2012 2012 Tsai et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Tsai, Yien Che
Leichner, Gil S.
Pearce, Margaret M. P.
Wilson, Gaye Lynn
Wojcikiewicz, Richard J. H.
Roitelman, Joseph
Weissman, Allan M.
Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system
title Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system
title_full Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system
title_fullStr Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system
title_full_unstemmed Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system
title_short Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system
title_sort differential regulation of hmg-coa reductase and insig-1 by enzymes of the ubiquitin-proteasome system
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510011/
https://www.ncbi.nlm.nih.gov/pubmed/23087214
http://dx.doi.org/10.1091/mbc.E12-08-0631
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