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Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl CoA reductase in lipid droplet-associated endoplasmic reticulum membranes.

Sterol-induced binding to Insigs in endoplasmic reticulum (ER) membranes triggers ubiquitination of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl CoA reductase. This ubiquitination, which is mediated by Insig-associated ubiquitin ligases gp78 and Trc8, is obligatory for extraction of reductase from lipid droplet-associated ER membranes into the cytosol for proteasome-mediated, ER-associated degradation (ERAD). In this study, we identify lipid droplet-associated, ancient, ubiquitous protein-1 (Aup1) as one of several proteins that copurify with gp78. RNA interference (RNAi) studies show that Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to lipid droplets and facilitates its binding to both gp78 and Trc8. The functional significance of these interactions is revealed by the observation that RNAi-mediated knockdown of Aup1 blunts sterol-accelerated ubiquitination of reductase, which appears to occur in lipid droplet-associated membranes and subsequent ERAD of the enzyme. In addition, Aup1 knockdown inhibits ERAD of Insig-1, another substrate for gp78, as well as that of membrane-bound precursor forms of sterol-regulatory, element-binding protein-1 and -2, transcription factors that modulate expression of genes encoding enzymes required for cholesterol synthesis. Considered together, these findings not only implicate a role for Aup1 in maintenance of intracellular cholesterol homeostasis, but they also highlight the close connections among ERAD, lipid droplets, and lipid droplet-associated proteins.

Pubmed ID: 23223569 RIS Download

Mesh terms: Amino Acid Sequence | Animals | CHO Cells | Carrier Proteins | Conserved Sequence | Cricetinae | Endoplasmic Reticulum | Endoplasmic Reticulum-Associated Degradation | Gene Knockdown Techniques | Humans | Hydrophobic and Hydrophilic Interactions | Hydroxymethylglutaryl CoA Reductases | Intracellular Membranes | Lipids | Molecular Sequence Data | Protein Transport | RNA Interference | Receptors, Autocrine Motility Factor | Receptors, Cell Surface | Ubiquitin-Conjugating Enzymes | Ubiquitination

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Associated grants

  • Agency: NHLBI NIH HHS, Id: P01 HL020948
  • Agency: NHLBI NIH HHS, Id: HL20948
  • Agency: NIGMS NIH HHS, Id: R01 GM090216
  • Agency: Howard Hughes Medical Institute, Id: GM090216
  • Agency: NIGMS NIH HHS, Id:

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