title: Glucose controls phosphoregulation of hydroxymethylglutaryl coenzyme A reductase through the protein phosphatase 2A-related phosphatase protein, Ppe1, and Insig in fission yeast.
abstract: HMG-CoA reductase (HMGR) catalyzes a rate-limiting step in sterol biosynthesis and is a key control point in the feedback inhibition that regulates this pathway. Through the action of the membrane protein Insig, HMGR synthesis and degradation are regulated to maintain sterol homeostasis. The fission yeast Schizosaccharomyces pombe encodes homologs of HMGR and Insig called hmg1(+) and ins1(+), respectively. In contrast to the mammalian system, Ins1 regulates Hmg1 by a nondegradative mechanism involving phosphorylation of the Hmg1 active site. Here, we investigate the role of the Ins1-Hmg1 system in coupling glucose sensing to regulation of sterol biosynthesis. We show that Ins1-dependent Hmg1 phosphorylation is strongly induced in response to glucose withdrawal and that HMGR activity is correspondingly reduced. We also find that inability to activate Hmg1 phosphorylation under nutrient limiting conditions results in overaccumulation of sterol pathway intermediates. Furthermore, we show that regulation of Hmg1 phosphorylation requires the protein phosphatase 2A-related phosphatase Ppe1 and its regulator Sds23. These results describe a mechanism by which cells tune the rate of sterol synthesis to match nutrient availability.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Burg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Espenshade
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D047468:Immunoprecipitation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000201:enzymology / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D029702:Schizosaccharomyces pombe Proteins; C103137:Sds23 protein, S pombe; D006903:Hydroxymethylglutaryl CoA Reductases; D000263:Adenylate Kinase; C106081:ppe1 protein, S pombe; D010749:Phosphoprotein Phosphatases; D005947:Glucose