Department of Life Sciences, Korea University, Seoul 136-701, Korea.
Nat Commun. 2013;4:2354. doi: 10.1038/ncomms3354.
Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/- mice show an elevated IRS-1 level with enhanced insulin signalling, which protects the MG53-/- mice from developing insulin resistance when challenged with a high-fat/high-sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.
肌联蛋白 53（MG53）通过靶向胰岛素受体底物 1（IRS-1）负调控骨骼成肌作用。在这里，我们表明 MG53 是一种泛素 E3 连接酶，它在 E2 连接酶 UBE2H 的帮助下诱导 IRS-1 的泛素化。破坏 MG53 的 E3 连接酶功能的分子操作会消除 IRS-1 的泛素化并增强骨骼成肌作用。来自 MG53-/- 小鼠的骨骼肌表现出 IRS-1 水平升高和胰岛素信号增强，这使 MG53-/- 小鼠在受到高脂肪/高蔗糖饮食挑战时免受胰岛素抵抗的发展。来自人类糖尿病患者和胰岛素抵抗小鼠的肌肉样本显示出 MG53 的正常表达，表明 MG53 表达的改变不是代谢紊乱发展的致病因素。因此，针对 MG53 和 IRS-1 之间相互作用的治疗干预可能是治疗与胰岛素抵抗相关的代谢疾病的新方法。
