Reactome | Interferon Signaling

Interferon Signaling

Stable Identifier

R-HSA-913531

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Interferons (IFNs) are cytokines that play a central role in initiating immune responses, especially antiviral and antitumor effects. There are three types of IFNs:Type I (IFN-alpha, -beta and others, such as omega, epsilon, and kappa), Type II (IFN-gamma) and Type III (IFN-lamda). In this module we are mainly focusing on type I IFNs alpha and beta and type II IFN-gamma. Both type I and type II IFNs exert their actions through cognate receptor complexes, IFNAR and IFNGR respectively, present on cell surface membranes. Type I IFNs are broadly expressed heterodimeric receptors composed of the IFNAR1 and IFNAR2 subunits, while the type II IFN receptor consists of IFNGR1 and IFNGR2. Type III interferon lambda has three members: lamda1 (IL-29), lambda2 (IL-28A), and lambda3 (IL-28B) respectively. IFN-lambda signaling is initiated through unique heterodimeric receptor composed of IFN-LR1/IF-28Ralpha and IL10R2 chains.
Type I IFNs typically recruit JAK1 and TYK2 proteins to transduce their signals to STAT1 and 2; in combination with IRF9 (IFN-regulatory factor 9), these proteins form the heterotrimeric complex ISGF3. In nucleus ISGF3 binds to IFN-stimulated response elements (ISRE) to promote gene induction.
Type II IFNs in turn rely upon the activation of JAKs 1 and 2 and STAT1. Once activated, STAT1 dimerizes to form the transcriptional regulator GAF (IFNG activated factor) and this binds to the IFNG activated sequence (GAS) elements and initiate the transcription of IFNG-responsive genes.
Like type I IFNs, IFN-lambda recruits TYK2 and JAK1 kinases and then promote the phosphorylation of STAT1/2, and induce the ISRE3 complex formation.

Literature References

PubMed ID	Title	Journal	Year
14525967	Interferon-gamma: an overview of signals, mechanisms and functions Schroder, K, Ravasi, T, Hume, DA, Hertzog, PJ	J Leukoc Biol	2004
15864272	Mechanisms of type-I- and type-II-interferon-mediated signalling Platanias, LC	Nat Rev Immunol	2005
18929502	IFNgamma signaling-does it mean JAK-STAT? Gough, DJ, Levy, DE, Clarke, CJ, Johnstone, RW	Cytokine Growth Factor Rev	2008
19059436	Interferons: signaling, antiviral and viral evasion Ferreira, PC, Bonjardim, CA, Kroon, EG	Immunol Lett	2009
15607020	Mechanisms of type-I interferon signal transduction Platanias, LC, Uddin, S	J Biochem Mol Biol	2004