Abstract
INSIGs are proteins that underlie sterol regulation of the mammalian proteins SCAP (SREBP cleavage activating protein) and HMG-CoA reductase (HMGR). The INSIGs perform distinct tasks in the regulation of these effectors: they promote ER retention of SCAP, but ubiquitin-mediated degradation of HMGR. Two questions that arise from the discovery and study of INSIGs are: how do they perform these distinct tasks, and how general are the actions of INSIGs in biology? We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. Nsg1p functions naturally to limit degradation of Hmg2p when both proteins are at native levels, indicating a long-standing functional interplay between these two classes of proteins. One way to unify the known, disparate actions of INSIGs is to view them as known adaptations of a chaperone dedicated to SSD-containing client proteins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Anticholesteremic Agents / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / metabolism
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
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Humans
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Hydroxymethylglutaryl CoA Reductases / genetics
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Hydroxymethylglutaryl CoA Reductases / metabolism*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
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Intracellular Signaling Peptides and Proteins
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Lovastatin / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism*
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Molecular Sequence Data
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Promoter Regions, Genetic
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
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Sequence Alignment
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Sterols / metabolism*
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Tricarboxylic Acids / metabolism
Substances
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Anticholesteremic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Membrane Proteins
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Molecular Chaperones
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Nsg1 protein, S cerevisiae
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Nsg2 protein, S cerevisiae
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Recombinant Fusion Proteins
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SREBP cleavage-activating protein
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Saccharomyces cerevisiae Proteins
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Sterols
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Tricarboxylic Acids
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squalestatin 1
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Lovastatin
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Hydroxymethylglutaryl CoA Reductases
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
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TDH3 protein, S cerevisiae