Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders

Nature. 2013 Feb 21;494(7437):375-9. doi: 10.1038/nature11834. Epub 2013 Jan 27.


Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes. Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal, the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Diabetes Mellitus, Type 2
  • Diet, High-Fat
  • Dyslipidemias / metabolism
  • Gene Deletion
  • Hypertension / metabolism
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Insulin* / metabolism
  • Male
  • Membrane Proteins
  • Metabolic Syndrome / enzymology
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / prevention & control
  • Mice
  • Obesity / chemically induced
  • Obesity / metabolism
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Receptor, Insulin / metabolism
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Carrier Proteins
  • Insulin
  • Insulin Receptor Substrate Proteins
  • MG53 protein, mouse
  • Membrane Proteins
  • Ubiquitin-Protein Ligases
  • Receptor, Insulin