Nuclear β-Arrestin1 Functions as a Scaffold for the Dephosphorylation of STAT1 and Moderates the Antiviral Activity of IFN-γ

Signal transducers and activators of transcription 1 (STAT1) is activated by tyrosine phosphorylation upon interferon-γ (IFN-γ) stimulation. Phosphorylated STAT1 translocates into nucleus to initiate the transcription of IFN-γ target genes that are important in mediating antiviral, antiproliferative...

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Bibliographic Details
Published in:Molecular cell 2008-09, Vol.31 (5), p.695-707
Main Authors: Mo, Wei, Zhang, Liang, Yang, Guohua, Zhai, Jianwei, Hu, Zhonghua, Chen, Yuelei, Chen, Xu, Hui, Lijian, Huang, Ruimin, Hu, Gengxi
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - metabolism
Arrestins - genetics
Arrestins - metabolism
beta-Arrestins
Cell Line
Cell Nucleus - metabolism
Gene Expression Regulation
Genes, Reporter
Humans
Interferon-gamma - genetics
Interferon-gamma - metabolism
Mice
Protein Binding
Protein Interaction Mapping
PROTEINS
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
SIGNALING
STAT1 Transcription Factor - genetics
STAT1 Transcription Factor - metabolism
Two-Hybrid System Techniques
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Summary:Signal transducers and activators of transcription 1 (STAT1) is activated by tyrosine phosphorylation upon interferon-γ (IFN-γ) stimulation. Phosphorylated STAT1 translocates into nucleus to initiate the transcription of IFN-γ 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 β-arrestin1 directly interacts with STAT1 in nucleus after IFN-γ treatment and accelerates STAT1 tyrosine dephosphorylation by recruiting TC45. Consequently, β-arrestin1 negatively regulates STAT1 transcription activity as well as the IFN-γ-induced gene transcription. Application of β-arrestin1 siRNA significantly enhances IFN-γ-induced antiviral response in vesicular stomatitis virus (VSV)-infected cells. Our results reveal that nuclear β-arrestin1, acting as a scaffold for the dephosphorylation of STAT1, is an essential negative regulator of IFN-γ signaling and participates in the IFN-γ-induced cellular antiviral response.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2008.06.017