cIAP2-mediated IGF2BP2 ubiquitination and degradation regulate cardiomyocyte apoptosis via stabilizing m⁶A-modified...

Ubiquitin-proteasome system (UPS) is a major degradation system that maintains cardiac proteostasis, thus displaying an indispensable role in coronary artery disease, including myocardial infarction (MI). However, the function and mechanism of ubiquitin ligases in MI remain unclarified. In this study, we reported that cIAP2 protein, an E3 ubiquitin ligase, was downregulated in MI tissue and oxygen-glucose deprivation (OGD)-treated cardiomyocytes (CMs). cIAP2 depletion promoted OGD-induced injury and apoptosis in CMs, while adeno-associated virus (AAV) serotype 9 mediated-cardiac specific cIAP2 overexpression inhibited myocardial injury in MI mice. Moreover, we identified IGF2BP2 as a novel substrate of cIAP2. Mechanistically, cIAP2 downregulation inhibited IGF2BP2 ubiquitination and proteasomal degradation, leading to the upregulation of IGF2BP2 protein, which subsequently enhanced OGD-induced injury and apoptosis by stabilizing BAX mRNA in an m⁶A-dependent manner. In addition, our results showed that CWI1-2, a small molecule inhibitor of IGF2BP2, alleviated myocardial injury in MI mice by inhibiting cardiomyocyte apoptosis. Altogether, our results indicate that cIAP2 is a ubiquitin E3 ligase of IGF2BP2. The downregulation of cIAP2 protein aggravates OGD-induced apoptosis and oxidative damage in CMs via IGF2BP2/BAX axis. These findings provide a potential therapeutic target for reducing cardiomyocyte loss in MI.