Pre-assembly of STAT4 with the human IFN-α/β receptor-2 subunit is mediated by the STAT4 N-domain
- 作者：Douglas R. Tyler ; Meredith E. Persky ; Loderick A. Matthews ; Sheuwen Chan ; J. David Farrar
- 关键词：T cells ; Cytokine receptors ; Signal transduction
- 刊名：Molecular Immunology
- 出版年：2007
- 期刊代码：112_01615890
- 类别：bio
- 出版时间：March 2007
- 卷：44
- 期：8
- 页码：1864-1872
- 文件大小：1013 K
摘要
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.