Pre-assembly of STAT4 with the human IFN-α/β receptor-2 subunit is mediated by the STAT4 N-domain

Douglas R. Tyler, Meredith E. Persky, Loderick A. Matthews, Sheuwen Chan, J. David Farrar

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


CD4+ T cells regulate adaptive responses to pathogens by secreting unique subsets of cytokines that mediate inflammatory processes. The innate cytokines IL-12 and IFN-α/β regulate type I responses and promote acute IFN-γ secretion through the activation of the STAT4 transcription factor. Although IL-12-induced STAT4 activation is a conserved pathway across species, IFN-α/β-dependent STAT4 phosphorylation does not occur as efficiently in mice as it does in human T cells. In order to understand this species-specific pathway for IFN-α/β-dependent STAT4 activation, we have examined the molecular basis of STAT4 recruitment by the human IFNAR. In this report, we demonstrate that the N-domain of STAT4 interacts with the cytoplasmic domain of the human, but not the murine IFNAR2 subunit. This interaction mapped to a membrane-proximal segment of the hIFNAR2 spanning amino acids 299-333. Deletion of this region within the hIFNAR2 completely abolishes IFN-α/β-dependent STAT4 tyrosine phosphorylation when expressed in human IFNAR2-deficient fibroblasts. Thus, the human IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation.

Original languageEnglish (US)
Pages (from-to)1864-1872
Number of pages9
JournalMolecular Immunology
Issue number8
StatePublished - Mar 2007


  • Cytokine receptors
  • Signal transduction
  • T cells

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology


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