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, Cheol Soo Choi, Peihui Lin, Malith Karunasiri, Tao Tan, Pu Duann, Hua Zhu, Jianjie Ma and Young-Gyu Ko ()
Additional contact information
Jae-Sung Yi: Korea University
Jun Sub Park: Korea University
Young-Mi Ham: Korea University
Nga Nguyen: Korea University
Na-Rae Lee: Korea University
Jin Hong: Korea University
Bong-Woo Kim: Korea University
Hyun Lee: Korea University
Chang-Seok Lee: Korea University
Byung-Cheon Jeong: Korea University
Hyun Kyu Song: Korea University
Hana Cho: Korea University
Yoon Ki Kim: Korea University
Jae-Seon Lee: Korea Institute of Radiological and Medical Sciences
Kyong Soo Park: Seoul National University College of Medicine
Haksub Shin: Yonsei University, Gangwon-Do
Inho Choi: Yonsei University, Gangwon-Do
Seung Hee Lee: College of Life Sciences, Gwangju Institute of Science and Technology
Woo Jin Park: College of Life Sciences, Gwangju Institute of Science and Technology
Shi-Young Park: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute
Cheol Soo Choi: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute
Peihui Lin: Davis Heart and Lung Research Institute, The Ohio State University
Malith Karunasiri: Davis Heart and Lung Research Institute, The Ohio State University
Tao Tan: Davis Heart and Lung Research Institute, The Ohio State University
Pu Duann: Davis Heart and Lung Research Institute, The Ohio State University
Hua Zhu: Davis Heart and Lung Research Institute, The Ohio State University
Jianjie Ma: Davis Heart and Lung Research Institute, The Ohio State University
Young-Gyu Ko: Korea University

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3354

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