TRB3 Links the E3 Ubiquitin Ligase COP1 to Lipid Metabolism

• Published in: Science (American Association for the Advancement of Science) 2006-06, Vol.312 (5781), p.1763-1766
• Main Authors: Qi, Ling, Heredia, Jose E, Altarejos, Judith Y, Screaton, Robert, Goebel, Naomi, Niessen, Sherry, MacLeod, Ian X, Liew, Chong Wee, Kulkarni, Rohit N, Bain, James, Newgard, Christopher, Nelson, Michael, Evans, Ronald M, Yates, John, Montminy, Marc
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - antagonists & inhibitors; Acetyl-CoA Carboxylase - metabolism; adipocytes; Adipocytes - metabolism; adipose tissue; Adipose Tissue - cytology; Adipose Tissue - metabolism; Adipose Tissue, Brown - cytology; Adipose Tissue, Brown - metabolism; animal proteins; Animals; Biological and medical sciences; Body fat; Cell Cycle Proteins - metabolism; Cell Line; Dietary Fats - administration & dosage; Energy Metabolism; enzyme inhibition; Enzymes; Fasting; Fatty acids; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Humans; ligases; Lipid Metabolism; Lipids; Lipids. Glycolipids; Lipolysis; messenger RNA; Metabolism; Metabolisms and neurohumoral controls; Mice; Mice, Transgenic; Nuclear Proteins - metabolism; obesity; Obesity - prevention & control; Oxidation-Reduction; Phosphorylation; protein degradation; Proteins; regulatory proteins; starvation; Thinness; transgenic animals; TRB3 protein; Tribbles 3 protein; Ubiquitin - metabolism; ubiquitin ligase; Ubiquitin-Protein Ligases - metabolism; ubiquitination; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Weight Gain
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1123374

During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating acetyl-coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis. Here, we describe a parallel pathway, in which the pseudokinase Tribbles 3 (TRB3), whose abundance is increased during fasting, stimulates lipolysis by triggering the degradation of ACC in adipose tissue. TRB3 promoted ACC ubiquitination through an association with the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1). Indeed, adipocytes deficient in TRB3 accumulated larger amounts of ACC protein than did wild-type cells. Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, these results demonstrate how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis.