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Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase.

Sterol-regulated ubiquitination is an obligatory step in ER-associated degradation (ERAD) of HMG CoA reductase, a rate-limiting enzyme in cholesterol synthesis. Accelerated degradation of reductase, one of several strategies animal cells use to limit production of cholesterol, requires sterol-induced binding of the enzyme to ER membrane proteins called Insigs. Once formed, the reductase-Insig complex is recognized by a putative membrane-associated ubiquitin ligase (E3) that mediates the reductase ubiquitination reaction. Here, we show that gp78, a membrane bound E3, binds to Insig-1 and is required for sterol-regulated ubiquitination of reductase. In addition, gp78 couples regulated ubiquitination to degradation of reductase by binding to VCP, an ATPase that plays a key role in recognition and degradation of ERAD substrates. The current results identify gp78 as the E3 that initiates sterol-accelerated degradation of reductase, and Insig-1 as a bridge between gp78/VCP and the reductase substrate.

Pubmed ID: 16168377


  • Song BL
  • Sever N
  • DeBose-Boyd RA


Molecular cell

Publication Data

September 16, 2005

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL20948
  • Agency: NHLBI NIH HHS, Id: HL70441

Mesh Terms

  • Adenosine Triphosphatases
  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Cricetinae
  • Humans
  • Hydroxymethylglutaryl CoA Reductases
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Models, Biological
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Autocrine Motility Factor
  • Receptors, Cytokine
  • Sterols
  • Ubiquitin
  • Ubiquitin-Protein Ligases