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.
Highlights
Mitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; 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
Striated muscle-specific MG53 acts as a double-edged sword, interacting with many partner proteins such as IRS-1, focal adhesion kinase (FAK), caveolin-3, cavin-1, nonmuscle myosin type IIA (NM-IIA), and
Skeletal and cardiac muscles lose their capacity for membrane repair in MG53Ϫ/Ϫ mice, leading to muscular dystrophy
Summary
Mitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; 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. The MG53 expression level is 3– 4-fold higher in the skeletal and cardiac muscle obtained from animal models with metabolic syndromes such as high blood pressure, obesity, and diabetes compared with that from control animals These data demonstrate that MG53 is a therapeutic target protein for treating insulin resistance. The extracellular administration of recombinant MG53 or gene delivery of MG53 improves membrane repair in skeletal muscle obtained from mice with muscular dystrophy [18, 19] Both functions of MG 53, as an E3 ligase for IRS-1 ubiquitination and a component for membrane repair, should be considered two sides of the same coin when developing therapies targeting MG53. We demonstrated that one MID compound disrupted molecular association of MG53 with IRS-1 and abolished MG53-induced IRS-1 ubiquitination and degradation in skeletal muscle, leading to elevated IRS-1 expression level and increased insulin signaling and glucose uptake
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