title: Response to interferons and antibacterial innate immunity in the absence of tyrosine-phosphorylated STAT1.
abstract: Signal transducer and activator of transcription 1 (STAT1) plays a pivotal role in the innate immune system by directing the transcriptional response to interferons (IFNs). STAT1 is activated by Janus kinase (JAK)-mediated phosphorylation of Y701. To determine whether STAT1 contributes to cellular responses without this phosphorylation event, we generated mice with Y701 mutated to a phenylalanine (Stat1(Y701F)). We show that heterozygous mice do not exhibit a dominant-negative phenotype. Homozygous Stat1(Y701F) mice show a profound reduction in Stat1 expression, highlighting an important role for basal IFN-dependent signaling. The rapid transcriptional response to type I IFN (IFN-I) and type II IFN (IFNγ) was absent in Stat1(Y701F) cells. Intriguingly, STAT1Y701F suppresses the delayed expression of IFN-I-stimulated genes (ISG) observed in Stat1(-/-) cells, mediated by the STAT2/IRF9 complex. Thus, Stat1(Y701F) macrophages are more susceptible to Legionella pneumophila infection than Stat1(-/-) macrophages. Listeria monocytogenes grew less robustly in Stat1(Y701F) macrophages and mice compared to Stat1(-/-) counterparts, but STAT1Y701F is not sufficient to rescue the animals. Our studies are consistent with a potential contribution of Y701-unphosphorylated STAT1 to innate antibacterial immunity.
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Majoros
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Platanitis
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Szappanos
authors.affiliation: Department of Molecular Genetics and Proteomics Core, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
authors.forename: HyeonJoo
authors.initials: H
authors.lastname: Cheon
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Claus
authors.initials: C
authors.lastname: Vogl
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Priyank
authors.initials: P
authors.lastname: Shukla
authors.affiliation: Department of Molecular Genetics and Proteomics Core, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.affiliation: Department for Biomedical Sciences, Institute of Pharmacology and Toxicology University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schreiber
authors.affiliation: Departments of Microbiology & Immunology and Medicine, Columbia University, New York, NY, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria thomas.decker@univie.ac.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D007113:Immunity, Innate; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D007372:Interferons / Q000378:metabolism*; D007877:Legionnaires' Disease / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015290:Second Messenger Systems
chemical_list: D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007372:Interferons; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494228:Isgf3g protein, mouse
keywords: STAT1; innate immunity; interferon; pathogen; phosphorylation