MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle.
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.
From the Division of Life Sciences and.
Hyun
H
Lee
From the Division of Life Sciences and.
Jung-Jin
JJ
Park
From the Division of Life Sciences and.
Nga
N
Nguyen
From the Division of Life Sciences and.
Jun Sub
JS
Park
From the Division of Life Sciences and.
Jin
J
Hong
From the Division of Life Sciences and.
Seung-Hyeob
SH
Kim
the Department of Chemistry, Korea University, Seoul, 02841, Korea.
Woon Young
WY
Song
the Department of Chemistry, Korea University, Seoul, 02841, Korea.
Hak Joong
HJ
Kim
the Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea, and.
Kwangman
K
Choi
the Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea, and.
Sungchan
S
Cho
the Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22212, Korea.
Jae-Seon
JS
Lee
From the Division of Life Sciences and kbw96@korea.ac.kr.
Bong-Woo
http://orcid.org/0000-0001-8767-9519
BW
Kim
From the Division of Life Sciences and ygko@korea.ac.kr.
Young-Gyu
YG
Ko
D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008868:Microtubule Proteins / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects*; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
D002352:Carrier Proteins; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008868:Microtubule Proteins; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; C558399:TRIM72 protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases
diabetes; drug discovery; insulin receptor substrate 1 (IRS-1); insulin resistance; skeletal muscle