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beta-arrestin-biased agonism of beta-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling #MMPMID29627294
Teoh JP; Bayoumi AS; Aonuma T; Xu Y; Johnson JA; Su H; Weintraub NL; Tang Y; Kim IM
J Mol Cell Cardiol 2018[May]; 118 (?): 225-236 PMID29627294show ga
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.
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J+Mol+Cell+Cardiol 2018 ; 118 (?): 225-236
