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 Park & 8 others Cheol Soo Choi, Peihui Lin, Malith Karunasiri, Tao Tan, Pu Duann, Hua Zhu, Jianjie Ma, Young-Gyu Ko

Research output: Contribution to journalArticle

69 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 Sep 3

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Insulin Receptor Substrate Proteins
insulin
Muscle Development
Ubiquitination
Insulin
Insulin Resistance
Ubiquitin-Protein Ligases
Muscle
mice
Metabolic Diseases
High Fat Diet
Nutrition
metabolic diseases
Sucrose
Skeletal Muscle
Fats
skeletal muscle
diets
sucrose
Muscles

ASJC Scopus subject areas

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

Cite this

MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. / Yi, Jae Sung; Park, Jun Sub; Ham, Young Mi; Nguyen, Nga; Lee, Na Rae; Hong, Jin; Kim, Bong Woo; Lee, Hyun; Lee, Chang Seok; Jeong, Byung Cheon; Song, Hyun Kyu; Cho, Hana; Kim, Yoon Ki; Lee, Jae Seon; Park, Kyong Soo; Shin, Haksub; Choi, Inho; Lee, Seung Hee; Park, Woo Jin; Park, Shi Young; Choi, Cheol Soo; Lin, Peihui; Karunasiri, Malith; Tan, Tao; Duann, Pu; Zhu, Hua; Ma, Jianjie; Ko, Young-Gyu.

In: Nature Communications, Vol. 4, 2354, 03.09.2013.

Research output: Contribution to journalArticle

Yi, JS, Park, JS, Ham, YM, Nguyen, N, Lee, NR, Hong, J, Kim, BW, Lee, H, Lee, CS, Jeong, BC, Song, HK, Cho, H, Kim, YK, Lee, JS, Park, KS, Shin, H, Choi, I, Lee, SH, Park, WJ, Park, SY, Choi, CS, Lin, P, Karunasiri, M, Tan, T, Duann, P, Zhu, H, Ma, J & Ko, Y-G 2013, 'MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling', Nature Communications, vol. 4, 2354. https://doi.org/10.1038/ncomms3354
Yi, Jae Sung ; Park, Jun Sub ; Ham, Young Mi ; Nguyen, Nga ; Lee, Na Rae ; Hong, Jin ; Kim, Bong Woo ; Lee, Hyun ; Lee, Chang Seok ; Jeong, Byung Cheon ; Song, Hyun Kyu ; Cho, Hana ; Kim, Yoon Ki ; Lee, Jae Seon ; Park, Kyong Soo ; Shin, Haksub ; Choi, Inho ; Lee, Seung Hee ; Park, Woo Jin ; Park, Shi Young ; Choi, Cheol Soo ; Lin, Peihui ; Karunasiri, Malith ; Tan, Tao ; Duann, Pu ; Zhu, Hua ; Ma, Jianjie ; Ko, Young-Gyu. / MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. In: Nature Communications. 2013 ; Vol. 4.
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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.",
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AU - Ko, Young-Gyu

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