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 RIS Download
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