Figure 2.

IFN-dependent and -independent ISG transcription mediated by complexes comprised unphosphorylated STATs. In addition to the classical IFN signaling pathway based on complexes of phosphorylated STAT proteins (early response—details Figure 1), evidence exists for the involvement of unphosphorylated versions of ISGF3 (U-ISGF3), GAF (U-STAT1), and STAT2/IRF9 (U-STAT2/IRF9), in maintaining basal expression of certain ISGs in unstimulated cells (IFN independent). In addition, these unphosphorylated complexes are instrumental in sustaining expression of ISGs in response to long-term IFN-I or IFN-II stimulation (IFN dependent), when the level of phosphorylated STAT proteins is decreasing, but de novo synthesized unphosphorylated STAT proteins accumulate and can be incorporated in unphosphorylated transcription factors (late response). Abbreviations: IFN, interferon; STAT, signal transducer and activator of transcription; IRF, interferon regulatory factor; JAK, Janus kinase; TYK, tyrosine kinase; ISGF3, interferon-stimulated gene factor 3; GAF, γ-activated factor; ISRE, interferon-stimulated response element; GAS, γ-activated sequence; ISG, interferon-stimulated gene; P, phosphate; U, unphosphorylated form.