MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling
Open Access
- 22 August 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 4 (1), 1-12
- https://doi.org/10.1038/ncomms3354
Abstract
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.Keywords
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