USP10 Deubiquitinates MTX2 to Suppress cGAS-STING Signaling in MI

Myocardial infarction (MI) results in 3 distinct regions within the left ventricle: the infarct zone, the border zone (BZ), and the remote zone. A major focus of MI research is investigating the intrinsic mechanisms in the BZ to alleviate myocardial injury. USP10 (ubiquitin-specific peptidase 10) expression is reduced in BZ cardiomyocytes, indicating potential for targeted therapeutic intervention.

Isolated BZ cardiomyocytes and hypoxia-treated neonatal rat cardiomyocytes were used to investigate the expression of USP10 in MI. Cultured neonatal rat cardiomyocytes and genetically engineered mice were used to assess the importance of USP10 in the context of MI. Immunoprecipitation mass spectrometry and ubiquitination assays were used to explore the mechanisms by which USP10 suppresses the cGAS (cyclic GMP-AMP synthase) stimulator of interferon genes (STING) pathway.

Our study reveals that USP10 is critical in protecting against cardiac injury following MI. Specifically, USP10 mitigates MI-induced mitochondrial dysfunction and prevents the release of mitochondrial DNA into the cytosol, thereby inhibiting the activation of the cGAS-STING signaling pathway. Additionally, USP10 deubiquitinates the K48-linked ubiquitination of MTX2 (metaxin 2), thus enhancing MTX2 protein stability. We identified K93 as a critical ubiquitination site on MTX2 through mutagenesis analysis. Importantly, our findings demonstrate that the MTX2-K93R mutation rectifies USP10 loss-induced exacerbation of MI.

This study identifies USP10 as a novel regulator of the cGAS-STING signaling pathway in MI. Moreover, our findings demonstrate that a decrease in USP10 in the BZ cardiomyocytes can be therapeutically targeted to mitigate cardiac injury in MI.