Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol.
Feedback control of cholesterol synthesis is mediated in part by sterol-induced binding of HMG CoA reductase to Insig proteins in the endoplasmic reticulum (ER). Binding leads to ubiquitination and proteasomal degradation of reductase, a rate-controlling enzyme in cholesterol synthesis. Using in vitro and in vivo assays, we show that lanosterol, the first sterol intermediate in cholesterol synthesis, potently stimulates ubiquitination of reductase, whereas cholesterol has no effect at 10-fold higher concentrations. Lanosterol is not effective in mediating the other action of Insigs, namely to promote ER retention of SCAP-SREBP complexes, a reaction that is mediated directly by cholesterol. A pair of methyl groups located in the C4 position of lanosterol confers this differential response. These data indicate that buildup of cholesterol synthesis intermediates represses the pathway selectively at reductase and reveal a previously unappreciated link between feedback inhibition of reductase and carbon flow through the cholesterol synthetic pathway.
Song
Bao-Liang
BL
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Javitt
Norman B
NB
DeBose-Boyd
Russell A
RA
D002461:Cell Line, Transformed; D002784:Cholesterol / Q000096:biosynthesis* / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007810:Lanosterol / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D025801:Ubiquitin / Q000378:metabolism
C108626:INSIG1 protein, human; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D025801:Ubiquitin; D007810:Lanosterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases