IFNap signal transduction

All cellular responses to IFNs require the interaction of the ligand with a low number of high-affinity, species-specific cell surface receptors. There are two types of IFN receptors: type I and type II. The functional type I IFN receptor is composed of at least two transmembrane subunits and permits the productive binding of IFNp and the many related subtypes of IFNa. IFNa/p subspecies differ considerably in their affinity for the receptor, which correlates with the level and type of biological activity. The type II receptor also consists of two subunits and specifically binds IFN7. The pathways activated by type I IFNs are slightly different from those activated by type II IFN, which will be discussed in the article on 'Interferon 7 receptor'. Interestingly, the signal transduction pathway used by type I and type II IFNs has become a prototype for signaling from many cytokine receptors.

In response to type I IFN, within minutes the IFNa/p receptor activates two members of the JAK or Janus family of cytoplasmic tyrosine kinases, TYK2 and JAK1, that constitutively associate with the receptor cytoplasmic tail. Activated kinases become autophosphorylated and phosphorylate the receptor on specific tyrosine residues, creating docking sites for the transcription factors STAT1 and STAT2, that are members of a family known as STAT (signal transducers and activators of transcription). The STAT1 and STAT2 proteins subsequently become rapidly activated by tyrosine phosphorylation at a single site catalyzed by JAK I and TYK2. This activation allows them to stably assemble into a STAT1-STAT2 heterodimer complex through specific src homology 2 (SH2) phos-photyrosyl interactions, and together with the DNA-binding subunit p48 (a member of the IRF family) join in the multiprotein complex ISGF3 (IFN-stimu-lated gene factor 3). ISGF3 translocates to the nucleus where it binds to the IFN-stimulated response element (ISRE; consensus sequence AGTTTCNNTTTCT/C, where N is any nucleotide) sequence in the promoters of IFN'a/p-inducible genes (ISG), to initiate transcription. In addition to ISGF3, several other protein factors have been identified which recognize the ISRE: IRF1, IRF2, IRF3, ICSBP

(IFN consensus binding protein), Pip (Pu.l interaction partner) (all members of the IRF family) and IBP I (ISRE-binding protein 1). Although these factors all bind specifically to the ISRE, ISGF3 has been shown to be the primary factor involved in the early transcriptional activation of ISGs. ISGF3 is induced very rapidly by IFNa/fi without novel protein synthesis. The kinetics of appearance and decline of ISGF3 and its lack of dependence on protein synthesis correlate with transcriptional activation and deactivation of ISGs. The precise role of the other ISRE-binding factors in the regulation of the ISGs, however, remains to be established.

Lately, a second class of early response ISG1 genes has been identified, that are activated by both type I and type II IFNs and contain an enhancer element known as gamma activated site (GAS; TTNNNNNAA). In response to both types of IFN, a transcription factor known as GAF (composed of a homodimer of phosphorylated ST ATI) binds the GAS and activates transcription. GAF, like ISGF3, is resident in the cytoplasm of untreated cells, is activated in response to type I and type II IFNs, and then quickly migrates to the nucleus and binds DNA. Activation of GAF correlates with transcriptional activation of GAS-containing genes.

Recently, disruption of the gene for STAT1 in embryonic stem cells and in mice revealed that the STAT1 protein is required for all transcriptional responses to IFN. ST ATI-deficient mice grow and develop similar to wild-type animals, but show comprised innate immunity to viral disease (Figure 1).

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