Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders

MG53 acts as an E3 ligase that targets the insulin receptor and IRS1 for ubiquitin-dependent degradation; when MG53 is upregulated, metabolic syndrome ensues. Muscle enzyme MG53 as drug target This paper reports the surprising finding that dysregulation of the muscle-specific E3 ligase mitsugumin (MG53) causes insulin resistance and metabolic disorders in mice. When MG53 is upregulated metabolic syndrome ensues; removal of MG53 leaves insulin signalling intact, and prevents diet-induced metabolic syndrome. This work identifies MG53 as a promising therapeutic target for the treatment of metabolic diseases such as type 2 diabetes and associated cardiovascular complications. Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes 1 . Although skeletal muscle accounts for 70–90% of insulin-stimulated glucose disposal 2 , 3 , the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.