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. © 2013 Macmillan Publishers Limited.
CITATION STYLE
Yi, J. S., Park, J. S., Ham, Y. M., Nguyen, N., Lee, N. R., Hong, J., … Ko, Y. G. (2013). MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nature Communications, 4. https://doi.org/10.1038/ncomms3354
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