Faculty of Biology, Technion Institute of Technology, Haifa, Israel.
Nat Commun. 2020 Mar 13;11(1):1381. doi: 10.1038/s41467-020-14895-9.
Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (γ-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin, because DGC-insulin receptor dissociation by plakoglobin downregulation reduces insulin signaling and causes atrophy. Furthermore, low insulin receptor activity in muscles from transgenic or fasted mice decreases plakoglobin-DGC-insulin receptor content on the plasma membrane, but not when plakoglobin is overexpressed. By masking β-dystroglycan LIR domains, plakoglobin prevents autophagic clearance of plakoglobin-DGC-insulin receptor co-assemblies and maintains their function. Our findings establish DGC as a signaling hub, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.
胰岛素受体的信号转导控制着与细胞生长和代谢相关的中枢生理功能。在这里，我们通过串联的天然蛋白复合物纯化方法和超分辨率 STED 显微镜显示，胰岛素受体的活性需要与肌肉中的基本结构模块——营养不良蛋白聚糖复合物（DGC）和桥粒成分斑联蛋白（γ-连环蛋白）结合。这种高分子质量组装体的完整性使骨骼肌对胰岛素敏感，因为斑联蛋白下调导致 DGC-胰岛素受体解离会降低胰岛素信号转导并引起萎缩。此外，转基因或禁食小鼠肌肉中的胰岛素受体活性降低会导致质膜上的斑联蛋白-DGC-胰岛素受体含量减少，但当斑联蛋白过表达时则不会。通过掩盖β-肌营养不良蛋白 LIR 结构域，斑联蛋白阻止了斑联蛋白-DGC-胰岛素受体复合物的自噬清除，并维持了其功能。我们的发现确立了 DGC 作为信号枢纽，并为 Duchenne 肌营养不良症中的胰岛素抵抗以及斑联蛋白突变引起的心肌病提供了可能的机制。
