PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity

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.

[1]  R. Sun,et al.  Transcription Program of Murine Gammaherpesvirus 68 , 2003, Journal of Virology.

[2]  B. Ryffel,et al.  Interferon gamma receptor deficient mice are resistant to endotoxic shock , 1994, The Journal of experimental medicine.

[3]  S. Dewilde,et al.  The STAT3 isoforms α and β have unique and specific functions , 2004, Nature Immunology.

[4]  Richard M. Ransohoff,et al.  Stat1-independent regulation of gene expression in response to IFN-γ , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Massimo Gadina,et al.  Cytokine Signaling in 2002 New Surprises in the Jak/Stat Pathway , 2002, Cell.

[6]  G. Stark,et al.  Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. , 2002, Trends in immunology.

[7]  J. Darnell,et al.  Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. , 1992, Science.

[8]  J. ten Hoeve,et al.  Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase , 2002, Molecular and Cellular Biology.

[9]  M. Goldsmith,et al.  JAK/STAT signaling by cytokine receptors. , 1998, Current opinion in immunology.

[10]  H. Yasuda,et al.  Involvement of PIAS1 in the sumoylation of tumor suppressor p53. , 2001, Molecular cell.

[11]  T. Wright,et al.  IFN-gamma induces a p91/Stat1 alpha-related transcription factor with distinct activation and binding properties. , 1995, Journal of immunology.

[12]  Erica S. Johnson,et al.  An E3-like Factor that Promotes SUMO Conjugation to the Yeast Septins , 2001, Cell.

[13]  Chilakamarti V. Ramana,et al.  Biologic consequences of Stat1-independent IFN signaling , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[15]  T. Arora,et al.  PIASx Is a Transcriptional Co-repressor of Signal Transducer and Activator of Transcription 4* , 2003, Journal of Biological Chemistry.

[16]  J. Carton,et al.  Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. , 1999, Virology.

[17]  J. Stewart,et al.  Rta of Murine Gammaherpesvirus 68 Reactivates the Complete Lytic Cycle from Latency , 2000, Journal of Virology.

[18]  K. Shuai,et al.  Regulation of JAK–STAT signalling in the immune system , 2003, Nature Reviews Immunology.

[19]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[20]  J. ten Hoeve,et al.  A transcriptional corepressor of Stat1 with an essential LXXLL signature motif , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Levy,et al.  Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock , 2003, Nature Immunology.

[22]  Richard S. Rogers,et al.  SUMO Modification of STAT1 and Its Role in PIAS-mediated Inhibition of Gene Activation* , 2003, Journal of Biological Chemistry.

[23]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[24]  O. Silvennoinen,et al.  PIAS proteins promote SUMO-1 conjugation to STAT1. , 2003, Blood.

[25]  T. Decker,et al.  IFNs and STATs in innate immunity to microorganisms. , 2002, The Journal of clinical investigation.

[26]  Kenji Nakanishi,et al.  SOCS-1 participates in negative regulation of LPS responses. , 2002, Immunity.

[27]  K. Pfeffer,et al.  Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. , 2003, Immunity.

[28]  B. Cochran,et al.  The SIF binding element confers sis/PDGF inducibility onto the c‐fos promoter. , 1990, The EMBO journal.

[29]  C. Schindler,et al.  Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF‐1 promoter to mediate induction by IFN alpha and IFN gamma, and is likely to autoregulate the p91 gene. , 1994, The EMBO journal.

[30]  H. Saitoh,et al.  Functional Heterogeneity of Small Ubiquitin-related Protein Modifiers SUMO-1 versus SUMO-2/3* , 2000, The Journal of Biological Chemistry.

[31]  B. Chait,et al.  DNA binding of in vitro activated Stat1 alpha, Stat1 beta and truncated Stat1: interaction between NH2‐terminal domains stabilizes binding of two dimers to tandem DNA sites. , 1996, The EMBO journal.

[32]  G. Cheng,et al.  Involvement of receptor-interacting protein 2 in innate and adaptive immune responses , 2002, Nature.

[33]  P Jay,et al.  Specific inhibition of Stat3 signal transduction by PIAS3. , 1997, Science.

[34]  D. Hilton,et al.  Negative regulators of cytokine signal transduction , 1999, Cellular and Molecular Life Sciences CMLS.

[35]  S. Müller,et al.  Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Warren S. Alexander,et al.  Suppressors of cytokine signalling (SOCS) in the immune system , 2002, Nature Reviews Immunology.

[37]  Govinda Rao,et al.  IRF3 mediates a TLR3/TLR4-specific antiviral gene program. , 2002, Immunity.

[38]  小島 裕正.  IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s) , 1996 .

[39]  D. Levy,et al.  Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease , 1996, Cell.

[40]  T. Decker,et al.  Cytoplasmic activation of GAF, an IFN‐gamma‐regulated DNA‐binding factor. , 1991, The EMBO journal.

[41]  D. Chang,et al.  Inhibition of Stat1-mediated gene activation by PIAS1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Juliana Xu,et al.  Activation of p53 by Protein Inhibitor of Activated Stat1 (PIAS1)* , 2002, The Journal of Biological Chemistry.

[43]  J. Darnell,et al.  Induction of the Ly-6A/E gene by interferon alpha/beta and gamma requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[44]  金城 市子.  SOCS1/JAB is a negative regulator of LPS-induced macrophage activation , 2003 .