Response to interferons and antibacterial innate immunity in the absence of tyrosine-phosphorylated STAT1

Andrea Majoros, Ekaterini Platanitis, Daniel Szappanos, HyeonJoo Cheon, Claus Vogl, Priyank Shukla, George R Stark, Veronika Sexl, Robert Schreiber, Christian Schindler, Mathias Mueller, Thomas Decker

    Research output: Contribution to journalArticle

    21 Citations (Scopus)
    8 Downloads (Pure)

    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.
    Original languageEnglish
    Pages (from-to)367-382
    Number of pages6
    JournalEMBO Reports
    Volume17
    Issue number3
    Early online date12 Feb 2016
    DOIs
    Publication statusPublished - 1 Mar 2016

    Keywords

    • Jak-Stat Signalling
    • Innate Immunity
    • ChIP-Seq
    • interferon
    • pathogen
    • phosphorylation
    • STAT1

    Fingerprint Dive into the research topics of 'Response to interferons and antibacterial innate immunity in the absence of tyrosine-phosphorylated STAT1'. Together they form a unique fingerprint.

    Cite this