Abstract
Interferon (IFN) activates the signal transducer and activator of transcription (STAT) pathway to regulate immune responses. The protein inhibitor of activated STAT (PIAS) family has been suggested to negatively regulate STAT signaling. To understand the physiological function of PIAS1, we generated Pias1−/− mice. Using PIAS1-deficient cells, we show that PIAS1 selectively regulates a subset of IFN-γ- or IFN-β-inducible genes by interfering with the recruitment of STAT1 to the gene promoter. The antiviral activity of IFN-γ or IFN-β was consistently enhanced by Pias1 disruption. Pias1−/− mice showed increased protection against pathogenic infection. Our data indicate that PIAS1 is a physiologically important negative regulator of STAT1 and suggest that PIAS1 is critical for the IFN-γ- or IFN-β-mediated innate immune responses.
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Acknowledgements
We thank R. Sun for antibodies to MHV-68 viral proteins; R. Schreiber for Jak1−/− cells; and J. Gao and B. Nguyen for technical assistance. Supported by the National Institutes of Health (K.S. and H.W.), American Cancer Society (K.S.) Howard Hughes Medical Institute (H.W.), Leukemia & Lymphoma Society (B.L.), National Institutes of Health–National Cancer Institute (training grant 5T32 CA009056 to S.M.), University of California at Los Angeles, (Sprague Jr. Fellowship to K.A.W.) and US Public Health Service (National Research Service award, GM07185 to K.A.W.).
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Supplementary information
Supplementary Fig. 1
Tyrosine phosphorylation of Stat1 and Stat2 by IFN-γ or IFN-β. (PDF 104 kb)
Supplementary Table 1
Genes hyperactivated in Pias null BMMs in response to IFNs. (PDF 34 kb)
Supplementary Table 2
Primers used in real time quantitative PCR (Q-PCR) assays. (PDF 59 kb)
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Liu, B., Mink, S., Wong, K. et al. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat Immunol 5, 891–898 (2004). https://doi.org/10.1038/ni1104
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DOI: https://doi.org/10.1038/ni1104
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