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
Peptide Biology Laboratories and Gene Expression Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Science. 2006 Jun 23;312(5781):1763-6. 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.
在禁食期间，循环中的儿茶酚胺浓度升高，部分通过使脂肪酸合成的限速酶乙酰辅酶A羧化酶（ACC）磷酸化并使其失活，从而促进脂肪组织中脂质储存的动员。在此，我们描述了一条平行途径，其中假激酶 Tribbles 3（TRB3）在禁食期间丰度增加，它通过触发脂肪组织中ACC的降解来刺激脂肪分解。TRB3通过与E3泛素连接酶组成型光形态建成蛋白1（COP1）结合促进ACC的泛素化。实际上，缺乏TRB3的脂肪细胞比野生型细胞积累了更多的ACC蛋白。由于在脂肪组织中表达TRB3的转基因小鼠因脂肪酸氧化增强而免受饮食诱导的肥胖，这些结果证明了磷酸化和泛素化途径如何汇聚于脂质代谢的关键调节因子以维持能量稳态。
