Sterol-induced dislocation of 3-Hydroxy-3-methylglutaryl coenzyme a reductase from endoplasmic reticulum membranes into the cytosol through a subcellular compartment resembling lipid droplets

Isamu Z. Hartman, Pingsheng Liu, John K. Zehmer, Katherine Luby-Phelps, Youngah Jo, Richard G W Anderson, Russell A. DeBose-Boyd

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Sterol-induced binding to Insigs in the endoplasmic reticulum (ER) allows for ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. This ubiquitination marks reductase for recognition by the ATPase VCP/p97, which mediates extraction and delivery of reductase from ER membranes to cytosolic 26 S proteasomes for degradation. Here, we report that reductase becomes dislocated from ER membranes into the cytosol of sterol-treated cells. This dislocation exhibits an absolute requirement for the actions of Insigs and VCP/p97. Reductase also appears in a buoyant fraction of sterol-treated cells that co-purifies with lipid droplets, cytosolic organelles traditionally regarded as storage depots for neutral lipids such as triglycerides and cholesteryl esters. Genetic, biochemical, and localization studies suggest a model in which reductase is dislodged into the cytosol from an ER subdomain closely associated with lipid droplets.

Original languageEnglish (US)
Pages (from-to)19288-19298
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number25
DOIs
StatePublished - Jun 18 2010

Fingerprint

Coenzymes
Sterols
Endoplasmic Reticulum
Cytosol
Oxidoreductases
Membranes
Lipids
Ubiquitination
Cells
Cholesterol Esters
Proteasome Endopeptidase Complex
Organelles
Adenosine Triphosphatases
Lipid Droplets
Molecular Biology
Triglycerides
Cholesterol
Degradation
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Sterol-induced dislocation of 3-Hydroxy-3-methylglutaryl coenzyme a reductase from endoplasmic reticulum membranes into the cytosol through a subcellular compartment resembling lipid droplets. / Hartman, Isamu Z.; Liu, Pingsheng; Zehmer, John K.; Luby-Phelps, Katherine; Jo, Youngah; Anderson, Richard G W; DeBose-Boyd, Russell A.

In: Journal of Biological Chemistry, Vol. 285, No. 25, 18.06.2010, p. 19288-19298.

Research output: Contribution to journalArticle

@article{1f6b8de4cc23407f9c054342247b6ae1,
title = "Sterol-induced dislocation of 3-Hydroxy-3-methylglutaryl coenzyme a reductase from endoplasmic reticulum membranes into the cytosol through a subcellular compartment resembling lipid droplets",
abstract = "Sterol-induced binding to Insigs in the endoplasmic reticulum (ER) allows for ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. This ubiquitination marks reductase for recognition by the ATPase VCP/p97, which mediates extraction and delivery of reductase from ER membranes to cytosolic 26 S proteasomes for degradation. Here, we report that reductase becomes dislocated from ER membranes into the cytosol of sterol-treated cells. This dislocation exhibits an absolute requirement for the actions of Insigs and VCP/p97. Reductase also appears in a buoyant fraction of sterol-treated cells that co-purifies with lipid droplets, cytosolic organelles traditionally regarded as storage depots for neutral lipids such as triglycerides and cholesteryl esters. Genetic, biochemical, and localization studies suggest a model in which reductase is dislodged into the cytosol from an ER subdomain closely associated with lipid droplets.",
author = "Hartman, {Isamu Z.} and Pingsheng Liu and Zehmer, {John K.} and Katherine Luby-Phelps and Youngah Jo and Anderson, {Richard G W} and DeBose-Boyd, {Russell A.}",
year = "2010",
month = "6",
day = "18",
doi = "10.1074/jbc.M110.134213",
language = "English (US)",
volume = "285",
pages = "19288--19298",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "25",

}

TY - JOUR

T1 - Sterol-induced dislocation of 3-Hydroxy-3-methylglutaryl coenzyme a reductase from endoplasmic reticulum membranes into the cytosol through a subcellular compartment resembling lipid droplets

AU - Hartman, Isamu Z.

AU - Liu, Pingsheng

AU - Zehmer, John K.

AU - Luby-Phelps, Katherine

AU - Jo, Youngah

AU - Anderson, Richard G W

AU - DeBose-Boyd, Russell A.

PY - 2010/6/18

Y1 - 2010/6/18

N2 - Sterol-induced binding to Insigs in the endoplasmic reticulum (ER) allows for ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. This ubiquitination marks reductase for recognition by the ATPase VCP/p97, which mediates extraction and delivery of reductase from ER membranes to cytosolic 26 S proteasomes for degradation. Here, we report that reductase becomes dislocated from ER membranes into the cytosol of sterol-treated cells. This dislocation exhibits an absolute requirement for the actions of Insigs and VCP/p97. Reductase also appears in a buoyant fraction of sterol-treated cells that co-purifies with lipid droplets, cytosolic organelles traditionally regarded as storage depots for neutral lipids such as triglycerides and cholesteryl esters. Genetic, biochemical, and localization studies suggest a model in which reductase is dislodged into the cytosol from an ER subdomain closely associated with lipid droplets.

AB - Sterol-induced binding to Insigs in the endoplasmic reticulum (ER) allows for ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. This ubiquitination marks reductase for recognition by the ATPase VCP/p97, which mediates extraction and delivery of reductase from ER membranes to cytosolic 26 S proteasomes for degradation. Here, we report that reductase becomes dislocated from ER membranes into the cytosol of sterol-treated cells. This dislocation exhibits an absolute requirement for the actions of Insigs and VCP/p97. Reductase also appears in a buoyant fraction of sterol-treated cells that co-purifies with lipid droplets, cytosolic organelles traditionally regarded as storage depots for neutral lipids such as triglycerides and cholesteryl esters. Genetic, biochemical, and localization studies suggest a model in which reductase is dislodged into the cytosol from an ER subdomain closely associated with lipid droplets.

UR - http://www.scopus.com/inward/record.url?scp=77953530388&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953530388&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.134213

DO - 10.1074/jbc.M110.134213

M3 - Article

VL - 285

SP - 19288

EP - 19298

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 25

ER -