FOXA2 potently represses NF-κB–dependent transcription from viral promoters in liver cells

For the SV40 early promoter, NF-κB binding sites were necessary and sufficient for FOXA2–dependent repression. Consistent with this, the DNA binding domain of FOXA2 was sufficient to mediate repression of NF-κB–driven promoters. EMSA and immunoblot analyses indicated that FOXA2 does not repress these promoters through direct competition with NF-κB for DNA binding.

Instead, FOXA2 expression was associated with reduced NF-κB protein abundance, at least in part through proteasome-dependent degradation, revealing a novel indirect mechanism by which FOXA2 constrains NF-κB–dependent transcription. Since many viruses, including SV40 and HIV-1, rely heavily on NF-κB activity to drive early gene expression and the transition from latency to productive infection, our findings suggest that FOXA2 may function as a host-derived, context-dependent restriction factor that limits viral gene expression in differentiated tissues.