Kim Chai-Wan, Moon Young-Ah, Park Sahng Wook, Cheng Dong, Kwon Hyock Joo, Horton Jay D
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9626-31. doi: 10.1073/pnas.1001292107. Epub 2010 May 10.
Acetyl-CoA carboxylase (ACC), the first committed enzyme in fatty acid (FA) synthesis, is regulated by phosphorylation/dephosphorylation, transcription, and an unusual mechanism of protein polymerization. Polymerization of ACC increases enzymatic activity and is induced in vitro by supraphysiological concentrations of citrate (> 5 mM). Here, we show that MIG12, a 22 kDa cytosolic protein of previously unknown function, binds to ACC and lowers the threshold for citrate activation into the physiological range (< 1 mM). In vitro, recombinant MIG12 induced polymerization of ACC (as determined by nondenaturing gels, FPLC, and electron microscopy) and increased ACC activity by > 50-fold in the presence of 1 mM citrate. In vivo, overexpression of MIG12 in liver induced ACC polymerization, increased FA synthesis, and produced triglyceride accumulation and fatty liver. Thus, in addition to its regulation by phosphorylation and transcription, ACC is regulated at a tertiary level by MIG12, which facilitates ACC polymerization and enhances enzymatic activity.
乙酰辅酶A羧化酶（ACC）是脂肪酸（FA）合成中的首个关键酶，受磷酸化/去磷酸化、转录以及一种独特的蛋白质聚合机制调控。ACC的聚合增加酶活性，且在体外由超生理浓度的柠檬酸盐（>5 mM）诱导。在此，我们表明MIG12（一种功能未知的22 kDa胞质蛋白）与ACC结合，并将柠檬酸盐激活的阈值降低至生理范围（<1 mM）。在体外，重组MIG12诱导ACC聚合（通过非变性凝胶、快速蛋白质液相色谱和电子显微镜测定），并在存在1 mM柠檬酸盐的情况下使ACC活性增加>50倍。在体内，肝脏中MIG12的过表达诱导ACC聚合，增加FA合成，并导致甘油三酯积累和脂肪肝。因此，除了受磷酸化和转录调控外，ACC还在三级水平上受MIG12调控，MIG12促进ACC聚合并增强酶活性。
