Insig regulates HMG-CoA reductase by controlling enzyme phosphorylation in fission yeast.
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.
Burg
John S
JS
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Powell
David W
DW
Chai
Raymond
R
Hughes
Adam L
AL
Link
Andrew J
AJ
Espenshade
Peter J
PJ
D000595:Amino Acid Sequence; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000378:metabolism*; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000254:growth & development; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological
C506119:Insig1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D029702:Schizosaccharomyces pombe Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D020928:Mitogen-Activated Protein Kinases; C095409:sty1 protein, S pombe; D048369:MAP Kinase Kinase 1