IRF9

IRF9, short for Interferon Regulatory Factor 9, is a transcriptional regulator belonging to the IRF family and a key component of the interferon-stimulated gene factor 3 (ISGF3) complex. In humans, the IRF9 gene encodes a protein of about 50 kilodaltons, commonly referred to as p48, which serves as the gamma subunit of ISGF3 alongside STAT1 and STAT2.

IRF9's central role is to facilitate type I interferon signaling. Following IFN-α or IFN-β stimulation, STAT1 and STAT2 become phosphorylated and form a heterodimer that recruits IRF9 to assemble the ISGF3 complex. This complex then translocates to the nucleus, where it binds interferon-stimulated response elements (ISREs) in promoters to drive transcription of interferon-stimulated genes (ISGs). IRF9 provides the specificity and docking within this complex through its N-terminal DNA-binding–like domain and a C-terminal IRF association domain that mediates interactions with STAT proteins and other cofactors. While IRF9 itself has limited transactivation activity, it is essential as a co-activator in ISGF3-mediated transcription.

Regulation of IRF9 occurs at multiple levels and can be influenced by cell type and context. Its proper function is critical for robust antiviral responses; defects in IRF9 signaling can impair ISG induction and increase susceptibility to viral infections in experimental systems. Beyond canonical IFN signaling, IRF9 has been studied in various contexts of innate immunity and disease, including cancer and chronic infections, where its expression and activity may influence immune outcomes.

Alternative names for IRF9 include ISGF3 gamma and p48. The protein is conserved across vertebrates, underscoring its role in type I interferon signaling.