Mechanism Of Interferon Signaling

Interferons (IFNs) are cytokines, and, like retinoids, act as potent biological response modifiers. In humans, at least 26 IFN genes were originally classified into two groups according to the cell types in which they were found. Although the original classification has become obsolete, it is still in common use: IFN-a and IFN-P are type I and IFN-y is type II (50). A newer classification system designates IFN-a as a leukocyte IFN, IFN-P as fibroblast IFN, and IFN-y as immune IFN (51). IFNs were originally discovered as mediators of an antiviral state in virus-infected cells. It is now well established that IFNs also regulate proliferation, differentiation, and immune functions (50). IFNs bind to transmembrane glycoprotein receptors belonging to a subclass (class II) of a large family of cytokine receptors (52, Fig. 1). IFN binding mediates oligomerization of receptor subunits, which results in their reciprocal tyrosine phosphorylation (53). This is followed by a series of three phosphorylation events:

1. Phosphorylation and activation of a receptor-associated tyrosine kinases of the JAK (Janus kinase) family;

2. Phosphorylation of tyrosines on the cytoplasmic tail of the receptor and subsequent attachment of latent cytoplasmic transcription factors called signal transducing activators of transcription (STATs) to those phosphotyrosine sites; and

3. Phosphorylation of the STATs by the associated JAKs (see ref. 54 for review).

Phosphorylation of STATs results in their translocation to the nucleus, where they can modulate the transcription of a large number of genes (54; Fig. 1). In the case of IFN-a family members, binding to the interferon-a receptor-2 (IFNAR-2) subunit triggers dimer-ization with IFNAR-1 and phosphorylation of JAK1 and another JAK family member, Tyk2 (55-57; Fig. 1). JAK1 and Tyk2 subsequently phosphorylate and activate first STAT2 and then STAT1 (58). After translocation to the nucleus, these proteins form a transcription factor complex with a third protein, p48. This complex is called IFN-stimulated gene factor 3 (ISGF-3) (59,60 and references therein). ISGF-3 binds to consensus DNA sequences designated IFN-stimulated response elements (ISREs) found in the promoters of most IFN a/p responsive genes and activates their transcription (59,60; Fig. 1). IFN-P also binds IFNAR-2, which subsequently dimerizes with a distinct cell surface receptor and activates gene expression through the same JAKs and STATs as IFN-a (50,54).

IFN-y binds as a dimer to two IFN-y receptor (IFNGR-1) molecules, which each dimerize with an IFNGR-2 subunit (61; Fig. 1). The IFN-y signal is then transduced to STAT1 by JAK1 and JAK2, each bound to IFNGR-1 and IFNGR-2, respectively. The phosphorylated STAT1 enters the nucleus, but instead of forming the ISGF3 complex as in the case of IFN-a/p signal transduction, activates transcription as a STAT1 homodimer by binding to IFN-y activated sites (GAS) (50,61; Fig. 1). GAS sequences are distinct from ISREs and are found in the promoters of a large number of genes (50,61).

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