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Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders

Nature volume 494, pages 375–379 (2013)Cite this article

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Abstract

Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes1. Although skeletal muscle accounts for 70–90% of insulin-stimulated glucose disposal2,3, the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.

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Figure 1: MG53 ablation protects mice against diet-induced metabolic syndrome.
Figure 2: MG53 ablation blocks diet-induced systemic insulin resistance.
Figure 3: Overexpression of MG53 triggers systemic insulin resistance and metabolic syndrome.
Figure 4: Regulation of muscle insulin signalling by MG53.
Figure 5: MG53 E3 ligase activates ubiquitination of the insulin receptor and IRS1.

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Acknowledgements

We thank H. P. Cheng, G. Feng, X. Fu and L. P. Wei for discussions, and S. L. Guo, T. Zhang, X. H. Wang, D. Y. Chen, J. Y. Peng, L. Huang, W. Q. Zhang, N. Hou, L. Pan, L. Chen and Y. L. Liu for their technical support. Special thanks to H. Takeshima and J. J. Ma for their support in providing MG53−/− mice. This work was supported by the National Basic Research Program of China (2012CB518000, 2013CB531200, 2012CB944501) and the National Natural Science Foundation of China (81070674, 81070116, 3/22/002 and 81130073).

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  1. Ruisheng Song, Wei Peng and Yan Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Medicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China

    Ruisheng Song, Wei Peng, Yan Zhang, Fengxiang Lv, Hong-Kun Wu, Jiaojiao Guo, Li Jin, Mao Zhang, Peng Jiang, Fenghua Liu, Shaoshuai Meng, Xiuqin Zhang, Ping Jiang, Chun-Mei Cao & Rui-Ping Xiao

  2. Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100083, China

    Ruisheng Song

  3. Institute of Sports Medicine, Peking University Third Hospital, Beijing 100191, China

    Yongxing Cao, Yanbin Pi & Xin Zhang

  4. Center for Life Sciences, Peking University, Beijing 100871, China

    Rui-Ping Xiao

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  1. Ruisheng Song
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Contributions

R.S., W.P. and Y.Z. are equally contributing first authors. R.S. generated the initial idea and conducted key experiments. R.S., W.P., Y.Z., C.-M.C. and R.-P.X. designed the study, analysed the data and wrote the manuscript. C.-M.C. and R.-P.X. interpreted significance of the study. R.S., W.P., Y.Z., F. Lv, H.-K.W., J.G., Y.C., Y.P., Xin Z., L.J., M.Z., Pe.J., F. Liu and S.M. performed the experiments. Pi.J. helped in the generation of MG53 transgenic mice. Xiu.Z. provided the nonhuman primate tissues.

Corresponding authors

Correspondence to Chun-Mei Cao or Rui-Ping Xiao.

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Song, R., Peng, W., Zhang, Y. et al. Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature 494, 375–379 (2013). https://doi.org/10.1038/nature11834

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