Sterol-induced dislocation of 3-hydroxy-3-methylglutaryl coenzyme A reductase from endoplasmic reticulum membranes into the cytosol through a subcellular compartment resembling lipid droplets.
Sterol-induced binding to Insigs in the endoplasmic reticulum (ER) allows for ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. This ubiquitination marks reductase for recognition by the ATPase VCP/p97, which mediates extraction and delivery of reductase from ER membranes to cytosolic 26 S proteasomes for degradation. Here, we report that reductase becomes dislocated from ER membranes into the cytosol of sterol-treated cells. This dislocation exhibits an absolute requirement for the actions of Insigs and VCP/p97. Reductase also appears in a buoyant fraction of sterol-treated cells that co-purifies with lipid droplets, cytosolic organelles traditionally regarded as storage depots for neutral lipids such as triglycerides and cholesteryl esters. Genetic, biochemical, and localization studies suggest a model in which reductase is dislodged into the cytosol from an ER subdomain closely associated with lipid droplets.
Hartman
Isamu Z
IZ
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 74390-9046, USA.
Liu
Pingsheng
P
Zehmer
John K
JK
Luby-Phelps
Katherine
K
Jo
Youngah
Y
Anderson
Richard G W
RG
DeBose-Boyd
Russell A
RA
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry
D008055:Lipids; D013261:Sterols; D025801:Ubiquitin; D006903:Hydroxymethylglutaryl CoA Reductases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
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