Interferons signal transduction

All interferon-stimulated genes are characterized by the presence of an associated interferon-stimulated response element (ISRE). Signal transduction culminates in the binding of specific regulatory factors to the ISRE, which stimulates RNA polymerase Il-mediated transcription of the interferon-sensitive genes. The induced gene products then mediate the antiviral, immunomodulatory and other effects characteristically induced by interferons. 

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PIAS Proteins. Figure 1 Reporter gene assay with an interferon-y-driven artificial promoter demonstrating the inhibitory transcriptional activity of increasing amounts of PIAS on STAT1 signal transduction. 

Gough DJ, Sabapathy K, Ko EY, Arthur HA, Schreiber RD, Trapani JA, Clarke CJ, Johnstone RW (2007) A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes. J Biol Chem 282 938-946 Guidotti LG, Chisari EV (2001) Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19 65-91... 

Some cytokine receptors can directly initiate signal transduction upon binding of ligand. In other cases additional elements are involved. For many receptors, the exact intracellular events triggered upon ligand binding remain to be elucidated. However, the molecular details of signal transduction pathways for others (e.g. the interferons) are now understood... 

The intracellular events triggered upon binding of type I or II interferons to their respective receptors are quite similar. The sequence of events, known as the JAK-STAT pathway, has been elucidated over the last few years. It has quickly become apparent that this pathway plays a prominent role in mediating signal transduction, not only for interferon, but also of many cytokines. 

The receptors for cytokines and interferons are the starting point for signal transduction chains that bring about an activation of transcription factors. The signaling pathway involves the Janus protein kinase and Stat transcription factors (see 11.1.4). Phosphoty-rosine-SH2 interactions are also involved in several steps of signal transduction here. 

It is assumed that the Jak kinases bind to a cytoplasmic section of the receptor, which is in the vicinity of the membrane and contains two conserved sequence elements, Box 1 and Box 2. Binding of the Jak kinases leads to their activation, a process linked to mutual phosphorylation of the Jak kinases (Fig. 11.6). Activation of the Jak kinases may take place in a homodimeric receptor complex or it may also occm in hetero-oligomeric complexes. The circumstances are comphcated in that two (or more) Jak kinases may associate at an activated receptor. Two different Jak kinases are required for signal transduction via interferon receptors (see Fig. 11.8). Furthermore, the different Jak kinases are specific for the corresponding receptors. 

Starting from the activated Jak kinases, a signaling pathway leads directly to transcription factors that are phosphorylated by the Jak kinases on tyrosine residues and activated for stimulation of transcription (review Horvath and Darnell, 1997). These transcription factors belong to a class of proteins known as Stat proteins (Stat = signal transducer and activator of transcription). At least seven different Stat proteins are known (Statl-4, StatSa, StatSb, Stat6). The first Stat proteins, Statl and Stat2, were foimd in association with signal transduction via interferon y. 

Fig. 11.8. Scheme of signal transduction via interferon a. The receptor for interferon a (IFNa) binds and activates the Jak kinases Jakl and Tykl. These phosphorylate the Stat factors Statl and Stat2, leading to formation of Statl-Stat2 heterodimers. The heterodimers are transported into the nucleus and bind to a corresponding DNA element known as ISRE (interferon stimulated response element). Another protein, p48, is also involved in transcription activation of the interferon regulated gene. 

Greenlund AC, Farrar MA, Viviano BL, Schreiber RD. Ligand induced interferon-gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p912). EMBO J 1994 13 1591-1600. 

Frohman EM, Vayuvegula B, Gupta S, van den Noort S (1988) Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (la) antigen expression on cultured astrocytes via beta-2-adrenergic signal transduction mechanisms. Proc. Natl. AcadSci. USA 85 1292-1296. 

Kotenko SV, Izotova LS, Pollack BP, et al. Other kinases can substitute for Jak2 in signal transduction by interferon-gamma. J Biol Chem 1996 271 17174-82. 

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