title: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase and T cell receptor alpha subunit are differentially degraded in the endoplasmic reticulum.
abstract: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) is located in the endoplasmic reticulum (ER) and responds to rapid degradation which is regulated by mevalonate or sterols. T cell antigen receptor alpha chain (TCR alpha) is also known to be rapidly degraded within the ER. In both cases, the membrane domains of the proteins have a crucial role in their rapid degradation. In order to investigate protein degradation in the ER, we compared the degradation of HMG-CoA reductase and TCR alpha in the same Chinese hamster ovary cells. Among the protease inhibitors tested, N-acetyl-leucyl-leucyl-methioninal blocks the degradation of HMG-CoA reductase and also inhibits the degradation of TCR alpha. On the other hand, N-tosyl-L-phenylalanine chloromethyl ketone and N-carbobenzoxy-L-phenylalanine chloromethyl ketone inhibit the degradation of TCR alpha but have no effect on the degradation of HMG-CoA reductase. Diamide, a thiol-oxidizing agent, blocks the degradation of both HMG-CoA reductase and TCR alpha. Perturbation of cellular Ca2+ attenuates the rapid degradation of HMG-CoA reductase but does not affect the degradation of TCR alpha. Furthermore, thapsigargin, a selective ER Ca(2+)-ATPase inhibitor, and Co2+, a potent Ca2+ antagonist, increase the half-life of HMG-CoA reductase but not that of TCR alpha. Energy inhibitors diminish the rapid degradation of HMG-CoA reductase but not that of TCR alpha. These results suggest that although HMG-CoA reductase and TCR alpha appear to be degraded in the same subcellular compartment, the mechanisms responsible for degradation differ.
authors.affiliation: Department of Biological Sciences, Stanford University, California 94305-5020.
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.forename: R D
authors.initials: RD
authors.lastname: Simoni
mesh_terms: D017485:1-Deoxynojirimycin; D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D020126:Brefeldin A; D016466:CHO Cells; D006224:Cricetinae; D003513:Cycloheximide / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D003958:Diamide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010957:Plasmids; D011480:Protease Inhibitors / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection
chemical_list: D000214:Acyl Coenzyme A; D003517:Cyclopentanes; D011480:Protease Inhibitors; D016693:Receptors, Antigen, T-Cell, alpha-beta; D003958:Diamide; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D017485:1-Deoxynojirimycin; D020126:Brefeldin A; D003513:Cycloheximide; D005944:Glucosamine