Nuclear beta-arrestin1 functions as a scaffold for the dephosphorylation of STAT1 and moderates the antiviral activity of IFN-gamma

Mol Cell. 2008 Sep 5;31(5):695-707. doi: 10.1016/j.molcel.2008.06.017.


Signal transducers and activators of transcription 1 (STAT1) is activated by tyrosine phosphorylation upon interferon-gamma (IFN-gamma) stimulation. Phosphorylated STAT1 translocates into nucleus to initiate the transcription of IFN-gamma target genes that are important in mediating antiviral, antiproliferative, and immune response. The inactivation of STAT1 is mainly accomplished via tyrosine dephosphorylation by the nuclear isoform of T cell protein tyrosine phosphatase (TC45) in nucleus. Here we show that beta-arrestin1 directly interacts with STAT1 in nucleus after IFN-gamma treatment and accelerates STAT1 tyrosine dephosphorylation by recruiting TC45. Consequently, beta-arrestin1 negatively regulates STAT1 transcription activity as well as the IFN-gamma-induced gene transcription. Application of beta-arrestin1 siRNA significantly enhances IFN-gamma-induced antiviral response in vesicular stomatitis virus (VSV)-infected cells. Our results reveal that nuclear beta-arrestin1, acting as a scaffold for the dephosphorylation of STAT1, is an essential negative regulator of IFN-gamma signaling and participates in the IFN-gamma-induced cellular antiviral response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / metabolism*
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism*
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Mice
  • Protein Binding
  • Protein Interaction Mapping
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Two-Hybrid System Techniques
  • beta-Arrestins


  • Antiviral Agents
  • Arrestins
  • Recombinant Fusion Proteins
  • STAT1 Transcription Factor
  • beta-Arrestins
  • Interferon-gamma