A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription.
Chromatin modification is considered to be a fundamental mechanism of regulating gene expression to generate coordinated responses to environmental changes, however, whether it could be directly regulated by signals mediated by G protein-coupled receptors (GPCRs), the largest surface receptor family, is not known. Here, we show that stimulation of delta-opioid receptor, a member of the GPCR family, induces nuclear translocation of beta-arrestin 1 (betaarr1), which was previously known as a cytosolic regulator and scaffold of GPCR signaling. In response to receptor activation, betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300, resulting in enhanced local histone H4 acetylation and transcription of these genes. Our results reveal a novel function of betaarr1 as a cytoplasm-nucleus messenger in GPCR signaling and elucidate an epigenetic mechanism for direct GPCR signaling from cell membrane to the nucleus through signal-dependent histone modification.
Kang
Jiuhong
J
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School, Chinese Academy of Sciences, Shanghai 200031, China.
Shi
Yufeng
Y
Xiang
Bin
B
Qu
Bin
B
Su
Wenjuan
W
Zhu
Min
M
Zhang
Min
M
Bao
Guobin
G
Wang
Feifei
F
Zhang
Xiaoqing
X
Yang
Rongxi
R
Fan
Fengjuan
F
Chen
Xiaoqing
X
Pei
Gang
G
Ma
Lan
L
D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D050880:p300-CBP Transcription Factors / Q000378:metabolism
C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D002843:Chromatin; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D017465:Receptors, Opioid, delta; D011993:Recombinant Fusion Proteins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050880:p300-CBP Transcription Factors