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 journalArticlepeer-review

68 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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