β-Arrestin1-Biased β1-Adrenergic Receptor Signaling Regulates MicroRNA Processing
Rationale: MicroRNAs (miRs) are small, non-coding 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 following activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-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 β-arrestin-biased βAR agonist carvedilol activates cellular pathways in the heart.
Objective: Here, we tested whether carvedilol could activate β-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 β1AR-, G protein-coupled receptor kinase 5/6- and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs.
Conclusions: Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.
- β-arrestin-biased β-adrenergic receptor signaling
- microRNA biogenesis
- heart disease
- receptors, adrenergic, beta
- heart failure
- beta-adrenergic receptor blocker
- cell signaling
- Received October 2, 2013.
- Revision received December 9, 2013.
- Accepted December 13, 2013.