TY - JOUR
T1 - 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
AU - Hartman, Isamu Z.
AU - Liu, Pingsheng
AU - Zehmer, John K.
AU - Luby-Phelps, Katherine
AU - Jo, Youngah
AU - Anderson, Richard G W
AU - DeBose-Boyd, Russell A.
PY - 2010/6/18
Y1 - 2010/6/18
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.134213
DO - 10.1074/jbc.M110.134213
M3 - Article
C2 - 20406816
AN - SCOPUS:77953530388
SN - 0021-9258
VL - 285
SP - 19288
EP - 19298
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -