title: Insulin-induced gene protein (INSIG)-dependent sterol regulation of Hmg2 endoplasmic reticulum-associated degradation (ERAD) in yeast.
abstract: 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.
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, California 92093.
authors.forename: Chandra L
authors.initials: CL
authors.lastname: Theesfeld
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, California 92093. Electronic address: rhampton@ucsd.edu.
authors.forename: Randolph Y
authors.initials: RY
authors.lastname: Hampton
mesh_terms: D053898:Biosynthetic Pathways; D060746:Endoplasmic Reticulum-Associated Degradation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007810:Lanosterol / Q000378:metabolism / Q000502:physiology*; D008798:Mevalonic Acid / Q000378:metabolism; D018832:Molecular Chaperones / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology*; D013261:Sterols / Q000096:biosynthesis; D000077291:Terbinafine; D013729:Terpenes / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018832:Molecular Chaperones; D009281:Naphthalenes; C506541:Nsg1 protein, S cerevisiae; D011106:Polyisoprenyl Phosphates; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; D013729:Terpenes; D007810:Lanosterol; C541571:HMG2 protein, S cerevisiae; D006903:Hydroxymethylglutaryl CoA Reductases; D000077291:Terbinafine; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid