STAT (signal transducers and activators of transcription) proteins undergo cytokine-dependent phosphorylation on serine and tyrosine. STAT3, a transcription factor for acute phase response genes, was found to act as an adapter molecule in signal transduction from the type I interferon receptor. STAT3 bound to a conserved sequence in the cytoplasmic tail of the IFNAR1 chain of the receptor and underwent interferon-dependent tyrosine phosphorylation. The p85 regulatory subunit of phosphatidylinositol 3-kinase, which activates a series of serine kinases, bound to phosphorylated STAT3 and subsequently underwent tyrosine phosphorylation. Thus, STAT3 acts as an adapter to couple another signaling pathway to the interferon receptor.

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apoptosis ͉ viral infection

STAT proteins play critical roles in the signal transduction pathways for various cytokines. The type I interferons (IFN␣͞␤) promote the DNA-binding activity of the transcription factors STAT1, STAT2, and STAT3. Although the requirement for STAT1 and STAT2 in IFN␣͞␤ signaling and action is well documented, the biological importance of STAT3 to IFN action has not yet been addressed. We found that STAT3 plays a critical role in signal transduction by IFN␣͞␤. A human cell line that is resistant to the antiviral and antiproliferative activities of IFN but is still IFN-responsive by virtue of STAT1 and STAT2 activation was found to be defective in STAT3 activation and in induction of NF-B DNA-binding activity. Expression of STAT3 in these resistant cells complemented these signaling defects and also markedly increased cellular sensitivity to the antiviral and antiproliferative effects of IFN. Because STAT3 is involved in the induction of NF-B DNA-binding activity and in the induction of antiviral and antiproliferative activity, our results place STAT3 as an important upstream element in type I IFN signal transduction and in the induction of biological activities. Therefore, our results indicate that STAT1 and STAT2 are not the only STATs required for the expression of the key biological activities of IFN␣͞␤.Interferons (IFNs) are cytokines that block the viral infection of cells, inhibit cell proliferation, and modulate cell differentiation. Type I IFNs (IFN ␣, ␤, and ) compete with each other for binding to a common cell surface receptor, whereas the receptor for type II IFN (IFN␥) is a distinct entity (1). The type I IFN receptor is composed of IFNAR1 and IFNAR2 chains (2-4), which undergo rapid, ligand-dependent tyrosine phosphorylation. Although IFNAR2 is the ligand-binding subunit, IFNAR1 acts as a species-specific transducer for the actions of type I IFN (5-7). IFNs transduce signals from the cell surface resulting in selective gene activation (8-10) through the activation of JAK tyrosine kinases and signal transducers and activators of transcription (STAT) factors (11,12). Upon their tyrosine phosphorylation, IFN-activated STATs (STAT1, STAT2, and STAT3) dimerize and translocate to the nucleus.The crucial role that STAT1 and STAT2 play in the transcriptional response to IFN␣͞␤ and in the induction of antiviral activity has been demonstrated in knockout mice and in mutant human cell lines deficient in these proteins. However, the importance of STAT3 in IFN␣͞␤ action has been unresolved. For example, knockout of the STAT3 gene in mice leads to early embryonic lethality and STAT3-deficient cell lines could not be isolated (13). We recently reported that STAT3 acts as a bridge (adapter) for the IFN-dependent interaction of the IFNAR1 receptor chain and the regulatory 85-kDa (p85) subunit of phosphatidylinositol-3Ј (PI-3) kinase (14). PI-3 kinase is important in the regulation of many cellular events involving protein tyrosine kinases and is an upstream element in a serine kinase transduction cascade (15, 1...

IFN (2, 3). The crosslinking of 125I-IFNa to several human cell lines indicates that the IFNa/P receptor is a multiprotein complex, consisting of 95-, 115-, and 135-kDa subunits (3-5).Type I IFNs induce the transcription of specific early genes, the IFN-stimulated genes (ISGs), through the activation of the Jakl and Tyk2 protein-tyrosine kinases (PTKs) (6,7). PTK activation mediates the IFN-induced rapid tyrosine phosphorylation of the multiprotein latent cytosolic transcription factor ISGF3, which consequently translocates to the nucleus, where it interacts with conserved promoter elements in ISGs (8,9). This model of PTK activation resulting in the tyrosine phosphorylation of specific transcription factors and gene activation has been described for several cytokines (6,10,11) and serves as a paradigm for cytokine signaling. In contrast, the early events triggered by IFNa receptor occupancy and the functions of the various subunits are poorly characterized.A cDNA coding for one subunit (IFNaRl) of the human