Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders.
Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes. Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal, 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.
Institute of Molecular Medicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China.
Ruisheng
R
Song
Wei
W
Peng
Yan
Y
Zhang
Fengxiang
F
Lv
Hong-Kun
HK
Wu
Jiaojiao
J
Guo
Yongxing
Y
Cao
Yanbin
Y
Pi
Xin
X
Zhang
Li
L
Jin
Mao
M
Zhang
Peng
P
Jiang
Fenghua
F
Liu
Shaoshuai
S
Meng
Xiuqin
X
Zhang
Ping
P
Jiang
Chun-Mei
CM
Cao
Rui-Ping
RP
Xiao
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000378:metabolism; D017353:Gene Deletion; D006973:Hypertension / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D024821:Metabolic Syndrome / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D002352:Carrier Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D044767:Ubiquitin-Protein Ligases; D011972:Receptor, Insulin