title: Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity.
abstract: Stat1 is phosphorylated on serine 727 within its transactivating domain (TAD) in response to interferons or other immunological signals. We generated gene-targeted mutant mice expressing a serine727-alanine mutant of Stat1. These animals showed increased mortality upon infection with Listeria monocytogenes and impaired clearance of the bacteria from spleen and liver. The Stat1S727A mice were more resistant to the LPS-induced septic shock syndrome, suggesting that Stat1 serine phosphorylation promotes inflammatory responses. Expression of IFN-gamma-induced genes was strongly reduced in macrophages expressing Stat1(S727A). While mutation of Stat1 at S727 did not reduce its binding to chromatin, association with the coactivator CBP and histone acetylation at the interferon-responsive GBP promoter was strongly reduced, suggesting defective recruitment of histone acetylases as the mechanism underlying IFN-gamma hyporesponsiveness. Our data demonstrate that the increase in transcription factor activity caused by Stat serine phosphorylation contributes to macrophage activation and to IFN-gamma-dependent immune responses in vivo.
authors.affiliation: Max F Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Microbiology and Genetics, University of Vienna, Dr Bohr-Gasse 9/4, A1030 Vienna, Austria.
authors.forename: Louisa
authors.initials: L
authors.lastname: Varinou
authors.forename: Katrin
authors.initials: K
authors.lastname: Ramsauer
authors.forename: Marina
authors.initials: M
authors.lastname: Karaghiosoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Kolbe
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D012694:Serine; D007371:Interferon-gamma; D010770:Phosphotransferases