Insig regulates HMG-CoA reductase by controlling enzyme phosphorylation in fission yeast

Cell Metab. 2008 Dec;8(6):522-31. doi: 10.1016/j.cmet.2008.09.004.


Insig functions as a central regulator of cellular cholesterol homeostasis by controlling activity of HMG-CoA reductase (HMGR) in cholesterol synthesis. Insig both accelerates the degradation of HMGR and suppresses HMGR transcription through the SREBP-Scap pathway. The fission yeast Schizosaccharomyces pombe encodes homologs of Insig, HMGR, SREBP, and Scap, called ins1(+), hmg1(+), sre1(+), and scp1(+). Here, we characterize fission yeast Insig and demonstrate that Ins1 is dedicated to regulation of Hmg1, but not the Sre1-Scp1 pathway. Using a sterol-sensing domain mutant of Hmg1, we demonstrate that Ins1 binding to Hmg1 inhibits enzyme activity by promoting phosphorylation of the Hmg1 active site, which increases the K(M) for NADPH. Ins1-dependent phosphorylation of Hmg1 requires the MAP kinase Sty1/Spc1, and Hmg1 phosphorylation is physiologically regulated by nutrient stress. Thus, in fission yeast, Insig regulates sterol synthesis by a different mechanism than in mammalian cells, controlling HMGR phosphorylation in response to nutrient supply.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Hydroxymethylglutaryl CoA Reductases / biosynthesis
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Kinase 1 / metabolism
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Phosphorylation
  • Schizosaccharomyces / enzymology*
  • Schizosaccharomyces / growth & development
  • Schizosaccharomyces pombe Proteins / metabolism
  • Schizosaccharomyces pombe Proteins / physiology*
  • Stress, Physiological


  • Insig1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SREBP cleavage-activating protein
  • Schizosaccharomyces pombe Proteins
  • Hydroxymethylglutaryl CoA Reductases
  • Mitogen-Activated Protein Kinases
  • sty1 protein, S pombe
  • MAP Kinase Kinase 1