ADAR1p150 Forms a Complex with Dicer to Promote miRNA-222 Activity and Regulate PTEN Expression in CVB3-Induced Viral Myocarditis

Abstract

Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. However, the role of ADAR1p150 in vascular disease remains unclear. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene’s 3′-UTR, suggesting that miRNA-222 might play a regulatory role. In cultured cells, miR-222 suppressed PTEN expression. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC.

ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity

“…The specific roles of these isoforms are unknown at present and future studies are needed to understand the role of each of these isoforms in thyroid cancer. Curiously, it has been described that the interaction between ADAR1 p150 and DICER in viral myocarditis promotes the expression of specific miRNAs [53]. As we have previously demonstrated the important role of miR-146b in thyroid cancer as an oncogenic miRNA that inhibits PTEN [10] and DICER1 [54], the aforementioned interaction could be tested in our system to question whether the ADAR1-DICER1 complex promotes the activity of this miRNA in thyroid cancer.…”

The Role of Non-coding RNAs in Viral Myocarditis

“…Then the researchers confirmed miR-34a act as a pro-apoptotic molecule in VMC via targeting the SIRT1-p53 signaling pathway (Jiang et al, 2019 ). In contrast, miR-222, miR-98, and miR-21 may act as anti-apoptotic factors in VMC (He et al, 2013 ; Zhang B. Y. et al, 2016 ; Zhang X. et al, 2019 ). Zhang et al found that the expression of adenosine deaminase, RNA-specific (ADAR1) and miR-222 was increased in CVB3 induced VMC model, and the study in vitro showed that ADAR1 combined Dicer increased cell viability by inducing miR-222 synthesis which decreased the confirmed target phosphatase and tensin homolog (PTEN) expression (Zhang X. et al, 2019 ).…”

Genetic Basis of Myocarditis: Myth or Reality?

“…In cultured cells, miR-222 suppresses PTEN expression. These preliminary experimental studies suggest that ADAR1p150 could play a role in gene expression in viral myocarditis [281]. The cardiovascular impact of type I interferonopathies such as AGS (TREX1 and IFIH1 in particular) could go beyond possible myocardial inflammation and expand to primary pulmonary hypertension [282] as well as to the risk of coronary artery disease [283].…”