Article

Ancient Ubiquitous Protein-1 Mediates Sterol-Induced Ubiquitination of HMG CoA Reductase in Lipid Droplet-Associated Endoplasmic Reticulum Membranes.

From the Howard Hughes Medical Institute and the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
Molecular biology of the cell (Impact Factor: 5.98). 12/2012; DOI: 10.1091/mbc.E12-07-0564
Source: PubMed

ABSTRACT Sterol-induced binding to Insigs in endoplasmic reticulum (ER) membranes triggers ubiquitination of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl CoA reductase. This ubiquitination, which is mediated by Insig-associated ubiquitin ligases gp78 and Trc8, is obligatory for extraction of reductase from lipid droplet-associated ER membranes into the cytosol for proteasome-mediated ER-associated degradation (ERAD). Here, we identify lipid droplet-associated ancient ubiquitous protein-1 (Aup1) as one of several proteins that copurify with gp78. RNA interference (RNAi) studies show that Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to lipid droplets and facilitates its binding to both gp78 and Trc8. The functional significance of these interactions is revealed by the observation that RNAi-mediated knockdown of Aup1 blunts sterol-accelerated ubiquitination of reductase, which appears to occur in lipid droplet-associated membranes, and subsequent ERAD of the enzyme. In addition, Aup1 knockdown inhibits ERAD of Insig-1, another substrate for gp78, as well as that of membrane-bound precursor forms of sterol regulatory element-binding proteins-1 and 2, transcription factors that modulate expression of genes encoding enzymes required for cholesterol synthesis. Considered together, these findings not only implicate a role for Aup1 in maintenance of intracellular cholesterol homeostasis, but they also highlight the close connection between ERAD, lipid droplets, and lipid droplet-associated proteins.

0 Followers
 · 
85 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Proteomic studies have revealed many potential functions of cytoplasmic lipid droplets, and recent activity has confirmed that these bona fide organelles are central not only for lipid storage and metabolism, but for development, immunity, and pathogenesis by several microbes. There has been a burst of recent activity on the assembly, maintenance and turnover of lipid droplets that reveals fresh insights. This review summarizes several novel findings in initiation of lipid droplet assembly, protein targeting, droplet fusion, and turnover of droplets through lipophagy. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current Opinion in Cell Biology 02/2015; 33C:119-124. DOI:10.1016/j.ceb.2015.02.002 · 8.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD. - See more at: http://elifesciences.org/content/early/2015/03/05/eLife.05560#sthash.7nCiSPv9.dpuf
    eLife Sciences 03/2015; DOI:10.7554/eLife.05560#sthash.7nCiSPv9.dpuf · 8.52 Impact Factor

Full-text (2 Sources)

Download
11 Downloads
Available from
Oct 14, 2014