| First Author | Teoh JP | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 118 |
| Pages | 225-236 | PubMed ID | 29627294 |
| Mgi Jnum | J:261785 | Mgi Id | MGI:6151210 |
| Doi | 10.1016/j.yjmcc.2018.04.001 | Citation | Teoh JP, et al. (2018) beta-arrestin-biased agonism of beta-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. J Mol Cell Cardiol 118:225-236 |
| abstractText | RATIONALE: MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize beta-adrenergic receptor (betaAR) signaling, beta-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the beta-arrestin-biased betaAR ligand carvedilol, we previously showed that beta-arrestin1 (not beta-arrestin2)-biased beta1AR (not beta2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes beta-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. OBJECTIVE: Here, we investigate whether beta-arrestin-mediated betaAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling. METHODS AND RESULTS: In mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a beta-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on beta2ARs and beta1ARs, respectively. Mechanistically, beta-arrestin 1 or 2 regulates maturation of three newly identified betaAR/beta-arrestin-responsive miRs (beta-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of beta-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, beta-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets. CONCLUSIONS: Our findings indicate a novel role for betaAR-mediated beta-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms. |
