Blocking MG53^S255 Phosphorylation Protects Diabetic Heart From Ischemic Injury.

Content Provider	Europe PMC
Author	Lv, Fengxiang Wang, Yingfan Shan, Dan Guo, Sile Chen, Gengjia Jin, Li Zheng, Wen Feng, Han Zeng, Xiaohu Zhang, Shuo Zhang, Yan Hu, Xinli Xiao, Rui-Ping
Copyright Year	2022
Abstract	Background:As an integral component of cell membrane repair machinery, MG53 (mitsugumin 53) is important for cardioprotection induced by ischemia preconditioning and postconditioning. However, it also impairs insulin signaling via its E3 ligase activity-mediated ubiquitination-dependent degradation of IR (insulin receptor) and IRS1 (insulin receptor substrate 1) and its myokine function-induced allosteric blockage of IR. Here, we sought to develop MG53 into a cardioprotection therapy by separating its detrimental metabolic effects from beneficial actions.Methods:Using immunoprecipitation-mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we investigated the role of MG53 phosphorylation at serine 255 (S255). In particular, utilizing recombinant proteins and gene knock-in approaches, we evaluated the potential therapeutic effect of MG53-S255A mutant in treating cardiac ischemia/reperfusion injury in diabetic mice.Results:We identified S255 phosphorylation as a prerequisite for MG53 E3 ligase activity. Furthermore, MG53S255 phosphorylation was mediated by GSK3β (glycogen synthase kinase 3 beta) and markedly elevated in the animal models with metabolic disorders. Thus, IR-IRS1-GSK3β-MG53 formed a vicious cycle in the pathogenesis of metabolic disorders where aberrant insulin signaling led to hyper-activation of GSK3β, which in turn, phosphorylated MG53 and enhanced its E3 ligase activity, and further impaired insulin sensitivity. Importantly, S255A mutant eliminated the E3 ligase activity while retained cell protective function of MG53. Consequently, the S255A mutant, but not the wild type MG53, protected the heart against ischemia/reperfusion injury in db/db mice with advanced diabetes, although both elicited cardioprotection in normal mice. Moreover, in S255A knock-in mice, S255A mutant also mitigated ischemia/reperfusion-induced myocardial damage in the diabetic setting.Conclusions:S255 phosphorylation is a biased regulation of MG53 E3 ligase activity. The MG53-S255A mutant provides a promising approach for the treatment of acute myocardial injury, especially in patients with metabolic disorders.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC9770150&blobtype=pdf
ISSN	00097330
Journal	Circulation Research [Circ Res]
Volume Number	131
PubMed Central reference number	PMC9770150
Issue Number	12
PubMed reference number	36337049
e-ISSN	15244571
DOI	10.1161/circresaha.122.321055
Language	English
Publisher	Lippincott Williams & Wilkins
Publisher Date	2022-11-07
Publisher Place	Hagerstown, MD
Access Restriction	Open
Rights License	Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. © 2022 The Authors.
Subject Keyword	cardiac ischemia/reperfusion injury cardioprotection GSK3β insulin resistance MG53
Content Type	Text
Resource Type	Article
Subject	Physiology Cardiology and Cardiovascular Medicine