A Nuclear Function of beta-arrestin1 in GPCR Signaling: Regulation of Histone Acetylation and Gene Transcription

Cell. 2005 Dec 2;123(5):833-47. doi: 10.1016/j.cell.2005.09.011.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism*
  • Chromatin / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Epigenesis, Genetic
  • Gene Expression Regulation*
  • Histones / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Opioid, delta / genetics
  • Receptors, Opioid, delta / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • Transcription, Genetic*
  • beta-Arrestin 1
  • beta-Arrestins
  • p300-CBP Transcription Factors / metabolism

Substances

  • ARRB1 protein, human
  • Arrb1 protein, mouse
  • Arrestins
  • Chromatin
  • Histones
  • Proto-Oncogene Proteins c-fos
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid, delta
  • Recombinant Fusion Proteins
  • beta-Arrestin 1
  • beta-Arrestins
  • Cyclin-Dependent Kinase Inhibitor p27
  • p300-CBP Transcription Factors