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

doi:10.1074/jbc.M116.754424

MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle*

From the ^‡Division of Life Sciences and
the ^§Department of Chemistry, Korea University, Seoul, 02841, Korea,
the ^¶Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea, and
the ^‖Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22212, Korea

↵2 To whom correspondence may be addressed: Tunneling Nanotube Research Center, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul 02841, Korea. Tel.: 82-2-3290-4708; Fax: 82-2-927-9208; E-mail: kbw96{at}korea.ac.kr.
↵3 To whom correspondence may be addressed: Division of Life Sciences, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul 02841, Korea. Tel.: 82-2-3290-3453; Fax: 82-2-927-9208; E-mail: ygko{at}korea.ac.kr.

↵1 Both authors contributed equally to this work.
Edited by Jeffrey Pessin

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.

Footnotes

↵* This work was supported by a grant from the Korea of Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI14C2739; to Y.-G. K.). This work was also supported in part by a Korea University grant (to J.-J. P.). The authors declare that they have no conflicts of interest with the contents of this article.