Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase

Brittany M. Johnson, Russell A. DeBose-Boyd

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals.

Original languageEnglish (US)
JournalSeminars in Cell and Developmental Biology
DOIs
StateAccepted/In press - Jan 1 2017

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Endoplasmic Reticulum-Associated Degradation
Hydroxymethylglutaryl CoA Reductases
Ubiquitination
Sterols
Oxidoreductases
Endoplasmic Reticulum
Terpenes
Enzymes
Vitamin K 2
Membranes
Ligases
Ubiquitin
Cytosol
Membrane Proteins
Cholesterol
Liver

Keywords

  • Cholesterol
  • Endoplasmic reticulum (ER);
  • ER-associated degradation
  • Golgi
  • Isoprenoid
  • Prenyltransferase
  • Proteasome
  • Ubiquitin
  • Vitamin K

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

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title = "Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase",
abstract = "Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals.",
keywords = "Cholesterol, Endoplasmic reticulum (ER);, ER-associated degradation, Golgi, Isoprenoid, Prenyltransferase, Proteasome, Ubiquitin, Vitamin K",
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AU - DeBose-Boyd, Russell A.

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N2 - Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals.

AB - Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals.

KW - Cholesterol

KW - Endoplasmic reticulum (ER);

KW - ER-associated degradation

KW - Golgi

KW - Isoprenoid

KW - Prenyltransferase

KW - Proteasome

KW - Ubiquitin

KW - Vitamin K

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