A signaling hub of insulin receptor dystrophin glycoprotein complex and plakoglobin regulates muscle size

ABSTRACT: 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 (g-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin because DGC-insulin receptor dissociation by plakoglobin downregulation reduced insulin signaling and caused atrophy. Furthermore, low insulin receptor activity in muscles from transgenic or fasted mice decreased plakoglobin-DGC-insulin receptor content on the plasma membrane, but not when plakoglobin was overexpressed. By masking b-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.

OTHER RELATED OMICS DATASETS IN: MODEL1109130000 MODEL1311110000 MODEL1909260003 MODEL1311110001 MODEL1909260004 MODEL1703310000 MODEL1909260005 MODEL1909260006

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Tamar Ziv  

LAB HEAD: Shenhav Cohen

PROVIDER: PXD016989 | Pride | 2020-03-19

REPOSITORIES: Pride