Pre-assembly of STAT4 with the human IFN-alpha/beta receptor-2 subunit is mediated by the STAT4 N-domain.
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-alpha/beta regulate type I responses and promote acute IFN-gamma secretion through the activation of the STAT4 transcription factor. Although IL-12-induced STAT4 activation is a conserved pathway across species, IFN-alpha/beta-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-alpha/beta-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-alpha/beta-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.
Tyler
Douglas R
DR
Center for Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Persky
Meredith E
ME
Matthews
Loderick A
LA
Chan
Sheuwen
S
Farrar
J David
JD
D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013045:Species Specificity
C508033:IFNAR2 protein, human; C508034:Ifnar2 protein, mouse; D016898:Interferon-alpha; D046912:Multiprotein Complexes; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12; D016899:Interferon-beta