Journal of Biological Chemistry
Volume 275, Issue 4, 28 January 2000, Pages 2693-2697
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PROTEIN CHEMISTRY AND STRUCTURE
Recruitment of Stat4 to the Human Interferon-α/β Receptor Requires Activated Stat2*

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Stat4 activation is involved in differentiation of type 1 helper (Th1) T cells. Although Stat4 is activated by interleukin (IL)-12 in both human and murine T cells, Stat4 is activated by interferon (IFN)-α only in human, but not murine, CD4+ T cells. This species-specific difference in cytokine activation of Stat4 underlies critical differences in Th1 development in response to cytokines and is important to the interpretation of murine models of immunopathogenesis. Here, we sought to determine the mechanism of Stat4 recruitment and activation by the human IFN-α receptor. Analysis of phosphopeptide binding analysis suggests that Stat4 does not interact directly with tyrosine-phosphorylated amino acid residues within the cytoplasmic domains of either of the subunits of the IFN-α receptor complex. Expression of murine Stat4 in the Stat1-deficient U3A and the Stat2-deficient U6A cell lines shows that IFN-α-induced Stat4 phosphorylation requires the presence of activated Stat2 but not Stat1. Thus, in contrast to the direct recruitment of Stat4 by the IL-12 receptor, Stat4 activation by the human IFN-α receptor occurs through indirect recruitment by intermediates involving Stat2.

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This work was supported in part by National Institutes of Health Grant AIDK39676 and a grant from the Juvenile Diabetes Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Training Grant CA09547 in Cancer Biology from NCI, National Institutes of Health.