An Acetylation Switch Modulates the Transcriptional Activity of Estrogen-Related Receptor Alpha

Mol Endocrinol. 2010 Jul;24(7):1349-58. doi: 10.1210/me.2009-0441. Epub 2010 May 19.

Abstract

Posttranslational modifications are instrumental to achieve gene- and tissue-specific regulatory outcomes by transcription factors. Nuclear receptors are dynamically modulated by several types of posttranslational modifications including phosphorylation, methylation, acetylation, ubiquitination, and sumoylation. The estrogen-related receptor alpha (ERRalpha, NR3B1) is phosphorylated on multiple sites, and sumoylated in the amino-terminal region in a phosphorylation-dependent manner. Here we demonstrate that ERRalpha interacts with and is acetylated by p300 coactivator associated factor (PCAF) in vitro and in mouse liver. Purified PCAF acetylated the DNA-binding domain of ERRalpha on four highly-conserved lysines. In addition, coexpression of PCAF reduced the transcriptional activity of ERRalpha and, reciprocally, a deacetylase screen identified histone deacetylase 8 (HDAC8) and sirtuin 1 homolog (Sirt1) as independent enhancers of ERRalpha transcriptional function. HDAC8 and Sirt1 were also demonstrated to interact directly with ERRalpha in vivo and to deacetylate and increase the DNA binding affinity of ERRalpha in vitro. The removal of PCAF increases the DNA binding of ERRalpha in vivo, whereas the removal of Sirt1 and HDAC8 decreases it as assessed by chromatin immunoprecipitation assay. Altogether, our results show that ERRalpha is an acetylated protein and imply the existence of a dynamic acetylation/deacetylation switch involved in the control of ERRalpha transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mass Spectrometry
  • Mice
  • Protein Binding
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Transcription, Genetic / genetics*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*

Substances

  • ERRalpha estrogen-related receptor
  • Receptors, Estrogen
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sirt1 protein, mouse
  • Sirtuin 1
  • HDAC8 protein, mouse
  • Histone Deacetylases