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

Mol Cell. 2005 Sep 16;19(6):829-40. doi: 10.1016/j.molcel.2005.08.009.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Cell Cycle Proteins
  • INSIG1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Cytokine
  • Sterols
  • Ubiquitin
  • Hydroxymethylglutaryl CoA Reductases
  • AMFR protein, human
  • Receptors, Autocrine Motility Factor
  • Ubiquitin-Protein Ligases
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein