Type I Interferon Signaling Pathways

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Overview of Type I Interferon Signaling Pathways

Type I IFNs are produced following recognition of microbial products by cell surface and intracellular pattern recognition receptors. The type I interferon (IFN) family consists of multiple IFN-alpha subtypes, IFN-beta, IFN-delta, IFN-epsilon, IFN-kappa, IFN-tau, IFN-omega, and IFN-zeta/Limitin. IFN-alpha, IFN-beta, IFN-epsilon, IFN-kappa, and IFN-omega are all found in humans, while IFN-delta, IFN-tau, and IFN-zeta have only been described in pigs, cattle, and mice, respectively. No human homologues of these three type I interferon subclasses have been identified. All type I interferons have significant structural homology and bind to a common heterodimeric receptor consisting of the IFN-alpha/beta RI and IFN-alpha/beta R2 subunits, which are expressed on most cell types. Receptor engagement activates the IFN-alpha/beta R1-associated Tyk2 protein tyrosine kinase and the IFN-alpha/beta R2-associated Jak1 protein tyrosine kinase. These kinases subsequently regulate the phosphorylation and activation of different STAT proteins. Activated STAT proteins homo- or heterodimerize and translocate to the nucleus, where they promote the expression of numerous target genes. In addition, type I IFNs activate the MAPK, PI 3-K-Akt, and NF-kappa B signaling pathways. One transcriptional complex that is formed following stimulation by type I IFNs is the IFN-stimulated gene factor 3 (ISGF3) complex. This complex consists of phosphorylated STAT1, STAT2, and IRF9 and binds to IFN-stimulated response elements (ISREs) found in the promoters of numerous IFN-stimulated genes (ISGs). Other STAT homo- or heterodimers induced by type I IFNs bind to regulatory sequences in the promoters of target genes known as IFN-gamma-activated sequence (GAS) sites. Binding of STAT proteins to either ISREs or GAS sites regulates the expression of several hundred ISGs, which mediate the anti-viral, anti-proliferative, and apoptotic effects of type I IFNs.

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