A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in eukaryotes.
Sterol synthesis by the mevalonate pathway is modulated, in part, through feedback-regulated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). In both mammals and yeast, a non-sterol isoprenoid signal positively regulates the rate of HMGR degradation. To define more precisely the molecule that serves as the source of this signal, we have conducted both pharmacological and genetic manipulations of the mevalonate pathway in yeast. We now demonstrate that farnesyl diphosphate (FPP) is the source of the positive signal for Hmg2p degradation in yeast. This FPP-derived signal does not act by altering the endoplasmic reticulum degradation machinery in general. Rather, the FPP-derived signal specifically modulates Hmg2p stability. In mammalian cells, an FPP-derived molecule also serves as a positive signal for HMGR degradation. Thus, both yeast and mammalian cells employ the same strategy for regulation of HMGR degradation, perhaps by conserved molecular processes.
Gardner
R G
RG
Department of Biology, University of California, San Diego, La Jolla, California 92093, USA.
Hampton
R Y
RY
D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004795:Enzyme Stability; D005057:Eukaryotic Cells / Q000201:enzymology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051228:Geranyltranstransferase; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012717:Sesquiterpenes; D050603:Squalene Monooxygenase; D013729:Terpenes / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D011106:Polyisoprenyl Phosphates; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D013729:Terpenes; D014451:Ubiquinone; C004808:farnesyl pyrophosphate; D006903:Hydroxymethylglutaryl CoA Reductases; D010105:Oxygenases; D050603:Squalene Monooxygenase; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D008798:Mevalonic Acid