Type I interferon signaling pathway (IFN-I pathway) (IFN-I pathway)

The Type I interferon signaling pathway is a fundamental biological cascade that mediates the host's innate immune response to viral infections and other stressors. It is triggered by the binding of Type I interferons, including multiple IFN-α subtypes and IFN-β, to the ubiquitous Type I interferon receptor (IFNAR), a heterodimer composed of IFNAR1 and IFNAR2 subunits [1.1.2, 1.3.1]. This interaction activates the associated Janus kinases, JAK1 and TYK2, which phosphorylate Signal Transducer and Activator of Transcription (STAT) proteins, primarily STAT1 and STAT2 [1.1.4, 1.4.1]. These phosphorylated STATs associate with Interferon Regulatory Factor 9 (IRF9) to form the ISGF3 complex, which translocates to the nucleus and binds to Interferon-Stimulated Response Elements (ISRE) to drive the transcription of hundreds of Interferon-Stimulated Genes (ISGs) [1.3.1, 1.4.3]. These genes establish an antiviral state, inhibit cell proliferation, and modulate the activity of various immune cells, such as dendritic cells and T cells [1.1.1, 1.1.3]. In clinical practice, the pathway is targeted by agonists like recombinant IFN-α and IFN-β for treating viral hepatitis, multiple sclerosis, and certain cancers [1.1.3, 1.3.4]. Conversely, overactivation of the pathway is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE), leading to the development of antagonists such as anifrolumab, which blocks IFNAR1, and JAK inhibitors that interrupt downstream signaling [1.2.1, 1.4.2]. The pathway's complexity, involving multiple ligands and downstream effectors, allows for diverse biological outcomes but also presents challenges in achieving specific therapeutic effects without broad immunosuppression [1.2.2, 1.4.3].

Other names

Type I interferon pathwayIFN-alpha/beta signaling pathwayIFNAR signaling pathwayType I IFN signaling

Agonism of the Type I interferon receptor to induce antiviral and antitumor responses; Antagonism of the Type I interferon receptor or inhibition of downstream JAK/STAT signaling to suppress autoimmune inflammation.