title: STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways.
abstract: STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-γ, interleukin-6 (IL-6), and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-α binding. This, in turn, substantially attenuated cardinal IFN-γ responses, including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon-independent activities of this protein.
authors: School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors: Johnathan
authors: J
authors: Ho
authors: School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors: Christin
authors: C
authors: Pelzel
authors: School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors: Andreas
authors: A
authors: Begitt
authors: School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors: Maureen
authors: M
authors: Mee
authors: School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom.
authors: Hany M
authors: HM
authors: Elsheikha
authors: ISIS Spallation Neutron and Muon Source, Rutherford Appleton Laboratory, Didcot, United Kingdom.|Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, United Kingdom.|School of Biosciences, University of Nottingham, Nottingham, United Kingdom.
authors: David J
authors: DJ
authors: Scott
authors: School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors: Uwe
authors: U
authors: Vinkemeier
mesh_terms: D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D007371:Interferon-gamma; D004247:DNA