MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling

Jae Sung Yi, Jun Sub Park, Young Mi Ham, Nga Nguyen, Na Rae Lee, Jin Hong, Bong Woo Kim, Hyun Lee, Chang Seok Lee, Byung Cheon Jeong, Hyun Kyu Song, Hana Cho, Yoon Ki Kim, Jae Seon Lee, Kyong Soo Park, Haksub Shin, Inho Choi, Seung Hee Lee, Woo Jin Park, Shi Young ParkCheol Soo Choi, Peihui Lin, Malith Karunasiri, Tao Tan, Pu Duann, Hua Zhu, Jianjie Ma, Young Gyu Ko

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83 Citations (Scopus)

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.

Original languageEnglish
Article number2354
JournalNature communications
Volume4
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Yi, J. S., Park, J. S., Ham, Y. M., Nguyen, N., Lee, N. R., Hong, J., Kim, B. W., Lee, H., Lee, C. S., Jeong, B. C., Kyu Song, H., Cho, H., Kim, Y. K., Lee, J. S., Park, K. S., Shin, H., Choi, I., Lee, S. H., Park, W. J., ... Ko, Y. G. (2013). MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nature communications, 4, [2354]. https://doi.org/10.1038/ncomms3354