Noncanonical IFN Signaling: Mechanistic Linkage of Genetic and Epigenetic Events

Figure 3

The noncanonical model of IFNγ (a) and IFNα (b) signaling. (a) Binding of IFNγ to its receptor extracellular domain is followed by movement to IFNGR1 cytoplasmic domain in conjunction with endocytosis. The cytoplasmic binding increases the affinity of JAK2 for IFNGR1, which is the basis for its movement from IFNGR2 to IFNGR1. This results in autoactivation of the JAKs, phosphorylation of IFNGR1 cytoplasmic domain, and the binding and phosphorylation of STAT1α at IFNGR1. The complex of IFNγ/IFNGR1/STAT1α/JAK1/JAK2 undergoes active nuclear transport where the classic polycationic NLS of IFNγ plays a key role for this transport to genes in the nuclei that are specifically activated by IFNγ. JAKs are involved in epigenetic events that cause heterochromatin destabilization and promoter activation. Histone H3 phosphorylation at Tyr 41 by JAK1 and JAK2, indicated by arrows, is a key epigenetic event in IFNγ gene activation. (b) IFNα signaling involves the endocytosis of IFNα and both of its receptor subunits. This complex binds to p48 to generate interferon stimulated gene factor 3 (ISGF3). IFNα/IFNAR1/IFNAR2/JAK1/TYK2/p48 are then translocated to the promoter ISRE, where JAK1 and TYK2 are involved in phosphorylation of histone H3. GAS, IFN gamma activated sequence; H3, histone H3; ISRE, IFN sensitive response element; NPC, nuclear pore complex.

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