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; Young Gyu Ko

doi:10.1038/ncomms3354

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

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

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 language	English
Article number	2354
Journal	Nature Communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3354
State	Published - 2013
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by grants awarded to Y.-G.K. from the National Research Foundation (2011-0030158 and 2011-0017562) and to J.M. from the National Institutes of Health (HL069000 and AR061385).

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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, Article 2354. https://doi.org/10.1038/ncomms3354

@article{67819eb3d37746ac9bfa5655d6820c2c,

title = "MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling",

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.",

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

note = "Funding Information: This work was supported by grants awarded to Y.-G.K. from the National Research Foundation (2011-0030158 and 2011-0017562) and to J.M. from the National Institutes of Health (HL069000 and AR061385).",

year = "2013",

doi = "10.1038/ncomms3354",

language = "English",

volume = "4",

journal = "Nature Communications",

issn = "2041-1723",

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}

Yi, JS, Park, JS, Ham, YM, Nguyen, N, Lee, NR, Hong, J, Kim, BW, Lee, H, Lee, CS, Jeong, BC, Kyu Song, H, 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, YG 2013, 'MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling', Nature Communications, vol. 4, 2354. https://doi.org/10.1038/ncomms3354

TY - JOUR

T1 - MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling

AU - Yi, Jae Sung

AU - Park, Jun Sub

AU - Ham, Young Mi

AU - Nguyen, Nga

AU - Lee, Na Rae

AU - Hong, Jin

AU - Kim, Bong Woo

AU - Lee, Hyun

AU - Lee, Chang Seok

AU - Jeong, Byung Cheon

AU - Kyu Song, Hyun

AU - Cho, Hana

AU - Kim, Yoon Ki

AU - Lee, Jae Seon

AU - Park, Kyong Soo

AU - Shin, Haksub

AU - Choi, Inho

AU - Lee, Seung Hee

AU - Park, Woo Jin

AU - Park, Shi Young

AU - Choi, Cheol Soo

AU - Lin, Peihui

AU - Karunasiri, Malith

AU - Tan, Tao

AU - Duann, Pu

AU - Zhu, Hua

AU - Ma, Jianjie

AU - Ko, Young Gyu

N1 - Funding Information: This work was supported by grants awarded to Y.-G.K. from the National Research Foundation (2011-0030158 and 2011-0017562) and to J.M. from the National Institutes of Health (HL069000 and AR061385).

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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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U2 - 10.1038/ncomms3354

DO - 10.1038/ncomms3354

M3 - Article

C2 - 23965929

AN - SCOPUS:84883166199

SN - 2041-1723

VL - 4

JO - Nature Communications

JF - Nature Communications

M1 - 2354

ER -

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

Abstract

Bibliographical note

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