PRJNA731397
Irf7 orchestrates the immunological reaction in cardiomyocytes upon Adar1 deletion
Adenosine deaminases acting on RNA (Adar1 and Adar2) catalyze I-to-A RNA editing, a post-transcriptional mechanism involved in several cellular functions. However, the role of Adar1-dependent RNA editing in cardiomyocytes (CMs) remains unclear. Here we show that conditional deletion of Adar1 in CMs results in myocarditis progressively evolving into dilated cardiomyopathy and heart failure only after 6 months of age. Adar1 depletion drives activation of interferon signaling genes (ISGs) without apoptosis and cytokine activation, and reduces the hypertrophic response of CMs upon pressure overload. Interestingly, ablation of the cytosolic sensor MDA5 prevents cardiac ISG activation and delays disease onset, but does not rescue the long-term lethal phenotype elicited by conditional deletion of Adar1. However, retention of a single catalytically inactive Adar1 allele in CMs, in combination with MDA5 depletion, completely restores the cardiac function and prevents heart failure. Finally, ablation of interferon regulatory factor 7 (Irf7) attenuates the phenotype of Adar1-deficient CMs to a similar extent as MDA5 depletion, highlighting Irf7 as the main regulator of the immune response triggered by lack of Adar1 in CMs.