Nuclear beta-arrestin1 functions as a scaffold for the dephosphorylation of STAT1 and moderates the antiviral activity of IFN-gamma.
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.
Mo
Wei
W
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Zhang
Liang
L
Yang
Guohua
G
Zhai
Jianwei
J
Hu
Zhonghua
Z
Chen
Yuelei
Y
Chen
Xu
X
Hui
Lijian
L
Huang
Ruimin
R
Hu
Gengxi
G
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000071557:beta-Arrestins
D000998:Antiviral Agents; D019390:Arrestins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D000071557:beta-Arrestins; D007371:Interferon-gamma