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.
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, Cytokine, Sterols, Ubiquitin, Ubiquitin-Protein Ligases
Mol. Cell
Date: Sep. 16, 2005
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