TY - JOUR
T1 - β-arrestin-biased agonism of β-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling
AU - Teoh, Jian Peng
AU - Bayoumi, Ahmed S.
AU - Aonuma, Tatsuya
AU - Xu, Yanyan
AU - Johnson, John A.
AU - Su, Huabo
AU - Weintraub, Neal L.
AU - Tang, Yaoliang
AU - Kim, Il Man
N1 - Funding Information:
This work was supported by American Heart Association (AHA) Predoctoral Fellowship 16PRE30210016 to Jian-peng Teoh, National Institutes of Health (NIH) R01 HL124248 to Huabo Su, NIH R01 HL112640 and HL126949 to Neal L. Weintraub, NIH R01 HL086555 to Yaoliang Tang, NIH R01 HL134354 and AR070029 to Yaoliang Tang and Neal L. Weintraub, and American Physiological Society Shih-Chun Wang Young Investigator Award ( APHYS00008 ), AHA Grant-in-Aid 12GRNT12100048 and AHA Scientist Development Grant 14SDG18970040 , and NIH R01 HL124251 to Il-man Kim.
Funding Information:
This work was supported by American Heart Association (AHA) Predoctoral Fellowship 16PRE30210016 to Jian-peng Teoh, National Institutes of Health (NIH) R01 HL124248 to Huabo Su, NIHR01 HL112640 and HL126949 to Neal L. Weintraub, NIHR01 HL086555 to Yaoliang Tang, NIHR01 HL134354 and AR070029 to Yaoliang Tang and Neal L. Weintraub, and American Physiological Society Shih-Chun Wang Young Investigator Award (APHYS00008), AHA Grant-in-Aid12GRNT12100048 and AHA Scientist Development Grant14SDG18970040, and NIH R01HL124251 to Il-man Kim.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/5
Y1 - 2018/5
N2 - 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 β-adrenergic receptor (βAR) signaling, β-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the β-arrestin-biased βAR ligand carvedilol, we previously showed that β-arrestin1 (not β-arrestin2)-biased β1AR (not β2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes β-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. Objective: Here, we investigate whether β-arrestin-mediated βAR 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 β-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2ARs and β1ARs, respectively. Mechanistically, β-arrestin 1 or 2 regulates maturation of three newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of β-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, β-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets. Conclusions: Our findings indicate a novel role for βAR-mediated β-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.
AB - 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 β-adrenergic receptor (βAR) signaling, β-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the β-arrestin-biased βAR ligand carvedilol, we previously showed that β-arrestin1 (not β-arrestin2)-biased β1AR (not β2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes β-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. Objective: Here, we investigate whether β-arrestin-mediated βAR 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 β-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2ARs and β1ARs, respectively. Mechanistically, β-arrestin 1 or 2 regulates maturation of three newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of β-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, β-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets. Conclusions: Our findings indicate a novel role for βAR-mediated β-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.
KW - RNA binding proteins
KW - carvedilol
KW - dicer
KW - heart disease
KW - microRNA biogenesis
KW - β-arrestin-biased β-adrenergic receptor signaling
UR - http://www.scopus.com/inward/record.url?scp=85045429737&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045429737&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2018.04.001
DO - 10.1016/j.yjmcc.2018.04.001
M3 - Article
C2 - 29627294
AN - SCOPUS:85045429737
VL - 118
SP - 225
EP - 236
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -