Article

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

Center for Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Molecular Immunology (Impact Factor: 3). 04/2007; 44(8):1864-72. DOI: 10.1016/j.molimm.2006.10.006
Source: PubMed

ABSTRACT 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.

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    • "The signal transducer and activator of transcription 4 (STAT4) is one of the gene products involved in the IFNa signaling, and it can be activated and phosphorylated upon ligation of the type I IFN receptor by IFNa in monocytes, macrophages, DCs, and T lymphocytes [10]. Following activation, human STAT4 binds to regulatory regions of several genes to induce proinflammatory cell-mediated immunity [11]. "
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    • "Among gene products involved in the response to IFN-α, the STAT4 that interacts with the cytoplasmic part of the IFNAR (73) is strongly associated to SLE (74). In SLE patients there is an association between STAT4 genotype and a more severe phenotype, which includes nephritis and presence of anti-dsDNA autoantibodies (75,76). "
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    • "Among genes involved in the response to IFNα, the signal transducer and activator of transcription 4 (STAT4) that interacts with the cytoplasmic part of the type I interferon receptor (IFNAR) [43] is strongly associated with lupus [44]. In lupus patients there is an association between the STAT4 genotype, increased sensitivity to IFNα [45] and a more severe phenotype, which includes nephritis and the presence of anti-double-stranded DNA autoantibodies [46,47]. "
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