Abstract
Mitsugumin 53 (MG53) is a relatively newly identified tripartite motif-containing (TRIM) family muscle-specific E3 ubiquitin ligase that is expressed in skeletal muscle and the heart. It has been postulated to facilitate repair by targeting the site of an injury, and acting as a scaffold for assembly of a repair complex made up of dysferlin, annexin V, caveolin-3, and polymerase I and transcript release factor (PTRF). A recent letter published in Nature by Song et al. proposes an alternate function for MG53: as an E3 ligase that targets the insulin receptor and insulin receptor substrate 1 (IRS1) for degradation, therefore regulating muscle insulin signaling. This work is exciting, as it not only presents a novel role for MG53, but also suggests that muscle insulin signaling has a systemic influence on insulin resistance and the metabolic syndrome.
Highlights
Metabolic syndrome is a disorder of increasing prevalence, especially in developed countries; it is associated with an increase in the incidence of obesity and the often-associated type 2 diabetes
Specific inhibition of the E3 ubiquitin ligase activity of Mitsugumin 53 (MG53) by deletion of the RING finger domain or by mutation of a cysteine to an alanine at position 14 suppresses the effects of MG53 on insulin receptor activity and ubiquitination. This supports a model for MG53 targeting insulin receptor degradation via its E3 ubiquitination ligase activity; the downstream ubiquitination of insulin receptor substrate 1 (IRS1) seems dependent on the initial insulin receptor degradation, since IRS1 was not degraded upon IGF1 stimulation
It is interesting to speculate on how to reconcile its new identity as an E3 ubiquitin ligase that targets insulin signaling pathways with its canonical role as a membrane repair protein
Summary
Metabolic syndrome is a disorder of increasing prevalence, especially in developed countries; it is associated with an increase in the incidence of obesity and the often-associated type 2 diabetes. The skeletal muscle from MG53-null mice had increased Evans blue dye uptake after downhill running, suggesting that these mice have increased susceptibility to membrane injury. Further experiments by this group of researchers implicated MG53 as a central player in the repair of membrane damage; it acts by binding to phosphatidylserine at the damage site and acts as a scaffold to recruit a complex of repair proteins that includes dysferlin, annexin V, caveolin-3 and polymerase I and transcript release factor (PTRF) [5,7]. MG53 has been found to be upregulated in muscular dystrophy patients [8], no pathogenic MG53 mutations have been identified
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