Insulin-induced gene protein (INSIG)-dependent sterol regulation of Hmg2 endoplasmic reticulum-associated degradation (ERAD) in yeast.
Insulin-induced gene proteins (INSIGs) function in control of cellular cholesterol. Mammalian INSIGs exert control by directly interacting with proteins containing sterol-sensing domains (SSDs) when sterol levels are elevated. Mammalian 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR) undergoes sterol-dependent, endoplasmic-reticulum (ER)-associated degradation (ERAD) that is mediated by INSIG interaction with the HMGR SSD. The ... yeast HMGR isozyme Hmg2 also undergoes feedback-regulated ERAD in response to the early pathway-derived isoprene gernanylgeranyl pyrophosphate (GGPP). Hmg2 has an SSD, and its degradation is controlled by the INSIG homologue Nsg1. However, yeast Nsg1 promotes Hmg2 stabilization by inhibiting GGPP-stimulated ERAD. We have proposed that the seemingly disparate INSIG functions can be unified by viewing INSIGs as sterol-dependent chaperones of SSD clients. Accordingly, we tested the role of sterols in the Nsg1 regulation of Hmg2. We found that both Nsg1-mediated stabilization of Hmg2 and the Nsg1-Hmg2 interaction required the early sterol lanosterol. Lowering lanosterol in the cell allowed GGPP-stimulated Hmg2 ERAD. Thus, Hmg2-regulated degradation is controlled by a two-signal logic; GGPP promotes degradation, and lanosterol inhibits degradation. These data reveal that the sterol dependence of INSIG-client interaction has been preserved for over 1 billion years. We propose that the INSIGs are a class of sterol-dependent chaperones that bind to SSD clients, thus harnessing ER quality control in the homeostasis of sterols.
Mesh Terms:
Biosynthetic Pathways, Endoplasmic Reticulum-Associated Degradation, Enzyme Inhibitors, Hydroxymethylglutaryl CoA Reductases, Lanosterol, Mevalonic Acid, Molecular Chaperones, Naphthalenes, Polyisoprenyl Phosphates, Protein Binding, Protein Stability, Proteolysis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sterols, Terpenes
Biosynthetic Pathways, Endoplasmic Reticulum-Associated Degradation, Enzyme Inhibitors, Hydroxymethylglutaryl CoA Reductases, Lanosterol, Mevalonic Acid, Molecular Chaperones, Naphthalenes, Polyisoprenyl Phosphates, Protein Binding, Protein Stability, Proteolysis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sterols, Terpenes
J. Biol. Chem.
Date: Mar. 22, 2013
PubMed ID: 23306196
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