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  • Title: Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase.
    Author: Johnson BM, DeBose-Boyd RA.
    Journal: Semin Cell Dev Biol; 2018 Sep; 81():121-128. PubMed ID: 29107682.
    Abstract:
    Accelerated ubiquitination and subsequent endoplasmic reticulum (ER)-associated degradation (ERAD) constitute one of several mechanisms for feedback control of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This ERAD is initiated by the accumulation of certain sterols in ER membranes, which trigger binding of reductase to ER membrane proteins called Insigs. Insig-associated ubiquitin ligases facilitate ubiquitination of reductase, marking the enzyme for extraction across the ER membrane through a reaction that is augmented by nonsterol isoprenoids. Once extracted, ubiquitinated reductase becomes dislocated into the cytosol for degradation by 26S proteasomes. In this review, we will highlight several advances in the understanding of reductase ERAD, which includes the discovery for a role of the vitamin K2 synthetic enzyme UBIAD1 in the reaction and demonstration that sterol-accelerated ERAD significantly contributes to feedback regulation of reductase and cholesterol metabolism in livers of whole animals.
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