Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus

This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitinrelated domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I.C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-beta signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-beta 3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-beta 3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-beta production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-beta production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.