Arrestin1-Biased β1-Adrenergic Receptor Signaling Regulates MicroRNA Processing

Rationale: MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by -adrenergic receptors (ARs). Initially discovered to desensitize AR signaling, -arrestins are now appreciated to transduce multiple effector pathways independent of G-protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the -arrestin-biased AR agonist, carvedilol, activates cellular pathways in the heart. Objective: Here, we tested whether carvedilol could activate -arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects. Methods and Results: In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in (1)AR-, G-protein-coupled receptor kinase 5/6-, and -arrestin1-dependent manner. Mechanistically, -arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs. Conclusions: Our findings indicate a novel function for (1)AR-mediated -arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.