ISGF3

ISGF3, or interferon-stimulated gene factor 3, is a tripartite transcription factor complex that mediates the transcriptional response to type I interferons. It is formed by the proteins STAT1, STAT2, and IRF9 (also known as p48). When cells encounter type I interferons such as IFN-α or IFN-β, the receptors IFNAR1/IFNAR2 activate JAK kinases (JAK1 and TYK2), which phosphorylate STAT1 and STAT2. Phosphorylated STAT1 and STAT2 then form a heterodimer that recruits IRF9 to assemble the active ISGF3 complex. This complex translocates to the nucleus and binds to interferon-stimulated response elements (ISREs) in the promoters of interferon-stimulated genes (ISGs), driving their expression.

ISGF3 is a central driver of the antiviral state, regulating a broad suite of ISGs such as MX1, OAS, PKR, IFIT family members, and ISG15. This ISRE-driven response is distinct from the GAS element pathway, which largely relies on STAT1 homodimers in response to IFN-γ. The activity of ISGF3 is subject to regulation by cellular feedback mechanisms, including SOCS and PIAS proteins, and can be targeted by viral antagonists to impair host defense.

In research and clinical contexts, ISGF3 serves as a key marker of type I IFN signaling and is relevant to antiviral immunity, inflammatory and autoimmune conditions, and cancer immunology. The canonical ISGF3 pathway highlights the integrated role of STAT1, STAT2, and IRF9 in orchestrating inducible gene expression after type I interferon signaling.