Interferon Signaling

Interferons (IFN) are cytokines that play a central role in initiating immune responses, especially antiviral and antitumor effects. They are divided into three classes:Type I (predominantly IFN-α, -β and -κ), Type II (IFN-γ) and Type III (IFN-λ1 and -λ2 also known as IL-28 and IL-29). IFN receptors are transmembrane proteins that function as heterodimers. The Type I IFN receptor is made up of IFNAR1 and IFNAR2 while the type II IFN receptor consists of IFNGR1 and IFNGR2. Type I and Type II IFNs bind to IFNAR1 and IFNGR1 respectively while IFNAR2 and IFNGR2 subunits are involved in signal transduction. IFNAR2 and IFNGR2 activate tyrosine kinases JAK1, JAK2 or TYK2 which in turn phosphorylate the STAT proteins. STATs dimerize and translocate to the nucleus. In the case to Type I IFNs, STAT1-STAT2 heterodimers associate with IFN gene regulatory factor-9 (IRF-9). The resultant trimeric transcription factor, ISGF3, binds to the IFN-stimulated regulatory elements (ISREs) to induce the expression of many IFN-α/β-regulated genes. For Type II IFNs, STAT1 dimers bind to the γ-IFN-activated sequence (GAS) to drive IFN-γ induced gene expression.