Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols.
Sterol-regulated ubiquitination marks 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-determining enzyme in cholesterol synthesis, for endoplasmic reticulum (ER)-associated degradation by 26 S proteasomes. This degradation, which results from sterol-induced binding of reductase to ER membrane proteins called Insigs, contributes to the complex, multivalent feedback regulation of the enzyme. Degradation of HMG-CoA reductase is also stimulated by various forms of vitamin E, a generic term for alpha-, beta-, delta-, and gamma-tocopherols and tocotrienols, which are primarily recognized for their potent antioxidant activity. Here, we show that delta-tocotrienol stimulates ubiquitination and degradation of reductase and blocks processing of sterol regulatory element-binding proteins (SREBPs), another sterol-mediated action of Insigs. The gamma-tocotrienol analog is more selective in enhancing reductase ubiquitination and degradation than blocking SREBP processing. Other forms of vitamin E neither accelerate reductase degradation nor block SREBP processing. In vitro assays indicate that gamma- and delta-tocotrienol trigger reductase ubiquitination directly and do not require further metabolism for activity. Taken together, these results provide a biochemical mechanism for the hypocholesterolemic effects of vitamin E that have been observed in animals and humans.
Song
Bao-Liang
BL
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA. BLSONG@sibs.ac.cn
DeBose-Boyd
Russell A
RA
D002460:Cell Line; D002839:Chromans / Q000737:chemistry*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000737:chemistry* / Q000378:metabolism; D006937:Hypercholesterolemia / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013261:Sterols / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
D002839:Chromans; C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D013261:Sterols; D025801:Ubiquitin; D014810:Vitamin E; C082097:tocotrienol, delta; C013649:plastochromanol 8; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease