Interferon signaling pathways

Interferons (IFNs) encode a large family of multifunctional secreted protei ns that are involved in antiviral defense, the regulation of cell growth an d modulation of the immune response. They are subdivided into two types tha t activate transduction pathways via different cell surface receptors. Bind ing of both IFN type I and II results in the differential activation of JAK (Janus kinases) that phosphorylate latent cytoplasmic transcription factor s termed STATs (signal transducer and activator of transcription). Phosphor ylated STATs translocate to the nucleus, bind specific DNA elements and dir ect transcription, Type I IFN induces the phosphorylation of STAT1 and STAT 2 proteins by tyrosine phosphorylation involving the type I IFN receptor-as sociated tyrosine kinases TYK2 and JAK1. Following phosphorylation, STAT1 a nd STAT2 form the transcriptionally active IFN-stimulated gene factor 3 (IS GF3) by association with a protein of the IFN regulatory factor (IRF) famil y p48. The specificity of the transcriptional activation by ISGF3 is mediat ed by specific elements termed IFN-stimulatory response element (ISRE) loca ted in the promoter region of IFN-inducible genes. ISREs drive the expressi on of most IFN type I-regulated genes and a few IFN type II-regulated genes . Gene induction by type II IFN involves the phosphorylation of only STAT1 by JAK1 and JAK2 kinases. This phosphorylation generates a homodimer of STA T1 which is able to bind the IFN gamma-activated site (GAS) to activate tra nscription. This signaling is rapid and direct. Molecules involved in the I FN signaling pathways have been shown to be used by other polypeptide ligan ds in their own signal transduction pathways. Pathways other than JAK/STAT are also involved in IFN signaling, but their mechanisms are less clear. Th e best documented are the mitogen-activated protein kinase (MAPK) cascade t he components of the TCR (T cell receptor) signaling cascade and the Pi3 ki nase pathway.