MG53-IRS-1 (mitsugumin 53-insulin receptor substrate-1) interaction disruptor sensitizes insulin signaling in skeletal muscle

Hyun Lee, Jung Jin Park, Nga Nguyen, Jun Sub Park, Jin Hong, Seung Hyeob Kim, Woon Young Song, Hak Joong Kim, Kwangman Choi, Sungchan Cho, Jae Seon Lee, Bong Woo Kim, Young-Gyu Ko

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5 Citations (Scopus)

Abstract

Mitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; thus, an MG53-IRS-1 interaction disruptor (MID), which potentially sensitizes insulin signaling with an elevated level of IRS-1 in skeletal muscle, is an excellent candidate for treating insulin resistance. To screen for an MID, we developed a bimolecular luminescence complementation system using an N-terminal luciferase fragment fused with IRS-1 and a C-terminal luciferase fragment fused with an MG53 C14A mutant that binds to IRS-1 but does not have E3 ligase activity. An MID, which was discovered using the bimolecular luminescence complementation system, disrupted the molecular association of MG53 with IRS-1, thus abolishing MG53-mediated IRS-1 ubiquitination and degradation. Thus, the MID sensitized insulin signaling and increased insulin-elicited glucose uptake with an elevated level of IRS-1 in C2C12 myotubes. These data indicate that this MID holds promise as a drug candidate for treating insulin resistance.

Original languageEnglish
Pages (from-to)26627-26635
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number52
DOIs
Publication statusPublished - 2016 Dec 23

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, H., Park, J. J., Nguyen, N., Park, J. S., Hong, J., Kim, S. H., Song, W. Y., Kim, H. J., Choi, K., Cho, S., Lee, J. S., Kim, B. W., & Ko, Y-G. (2016). MG53-IRS-1 (mitsugumin 53-insulin receptor substrate-1) interaction disruptor sensitizes insulin signaling in skeletal muscle. Journal of Biological Chemistry, 291(52), 26627-26635. https://doi.org/10.1074/jbc.M116.754424