Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain.
Sterols accelerate degradation of the ER enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), which catalyzes a rate-controlling step in cholesterol biosynthesis. This degradation contributes to feedback inhibition of synthesis of cholesterol and nonsterol isoprenoids. Here, we show that degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1. Accelerated degradation is inhibited by overexpression of the sterol-sensing domain of SREBP cleavage-activating protein (SCAP), suggesting that both proteins bind to the same site on insig-1. Whereas insig-1 binding to SCAP leads to ER retention, insig-1 binding to HMG CoA reductase leads to accelerated degradation that is blocked by proteasome inhibitors. Insig-1 appears to play an essential role in the sterol-mediated trafficking of two proteins with sterol-sensing domains, HMG CoA reductase and SCAP.
Sever
Navdar
N
Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA.
Yang
Tong
T
Brown
Michael S
MS
Goldstein
Joseph L
JL
DeBose-Boyd
Russell A
RA
D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; C497387:SREBF1 protein, human; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid